Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[O:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[O:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1OCc1nc(-c2cccc([N+](=O)[O-])c2)oc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a solution of 3-methoxy-4-{[5-methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]methoxy}benzaldehyde (7.51 g) in tetrahydrofuran (100 mL)-ethanol (15 mL) was gradually added sodium borohydride (397 mg) at 0° C. After stirring at room temperature for 6 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (3-methoxy-4-{[5-methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]methoxy}phenyl)methanol as colorless crystals (5.92 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[C:3]=1[O:16][CH3:17].[OH-].[Na+].CO>C1COCC1.O>[I:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[O:16][CH3:17]
Reactant: COC(=O)c1cc2c(c(I)c1OC)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)cc2c(c1I)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a stirred solution of methyl 4-iodo-3-methoxy-5,6,7,8-tetrahydro-2-naphthalenecarboxylate (3.0 g, 8.67 mmol) in THF (12 mL) and H2O (4 mL) was added 10N NaOH (9 mL). Methanol was added dropwise until the cloudy solution became clear. After stirring overnight at room temperature, the THF was removed in vacuo. The aqueous solution was acidified to pH 2 with 1N HCl and resulting white precipitate was extracted with DCM (3×25 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford a light brown solid (2.8 g, 100%). 1H NMR (CDCl3) δ 7.83 (s, 1H), 3.92 (s, 3H), 2.77 (m, 4H), 1.78 (m, 4H). MS m/z 331 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccn1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccn1
Yield: 55.4 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (680 mg, 2 mmol) and 2-aminopyridine (200 mg, 2 mmol) to give 460 mg of the title compound (55%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (bs, 1H), 10.58 (s, 1H), 8.31 (d, 1H, J=4.6 Hz), 8.07 (t, 2H, J=8.1 Hz), 7.79 t, 1H, J=8.1 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.10 (dd, 1H, J=4.6, 8.1 Hz), 5.17~5.27 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.81 (dm, 1H, J=17.1 Hz), 2.76 (dd, 1H, J=13.5, 7.2 Hz), 2.57 (dd, 1H, J=13.5, 5.4 Hz), 2.07 (dm, 1H, J=13.5 Hz), 1.80~1.94 (m, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:18][CH2:17][N:9]2[C:10]3[C:15]([CH:16]=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[C:19](Cl)(=O)[C:20](Cl)=[O:21].Cl.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:36][C:37](=[NH:42])[O:38]C(C)C)=[CH:28]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([O:4][CH2:5][C@H:6]1[CH2:18][CH2:17][N:9]2[C:10]3[C:15]([C:16]([C:19]4[C:20](=[O:21])[NH:38][C:37](=[O:42])[C:36]=4[C:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]([CH3:26])[CH:28]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OC[C@H]1CCn2c(cc3ccccc32)C1
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
A stirred solution of 2.43 g (10 mmol) of (S)-8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido [1,2-a]indole (prepared as described in Example 2) in 15 ml of dichloromethane was treated at 0° C. with a solution of 1.27 g (10 mmol) of oxalyl chloride in 5 ml of dichloromethane. The solution was stirred for 15 minutes and then treated with 2.67 g (10 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride (prepared as described in Example 1) followed by 10 ml of dichloromethane. The mixture obtained was treated with 5.05 g (10 mmol) of triethylamine, allowed to warm to room temperature and stirred for 2 hours. The mixture was then washed with water and the organic layer was dried over magnesium sulfite and evaporated to dryness. The residue was dissolved in 30 ml of pyridine, cooled in ice and treated dropwise with 2.10 g (10 mmol) of trifluoroacetic anhydride over 2-3 minutes. After 15 minutes, the solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and 2M hydrochloric acid. The organic layer was washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfite and evaporated. The residue was triturated with 30 ml of methanol and the solid was removed by filtration. The product was washed with methanol and dried to give 2.45 g (52%) of (S)-3-[8-(acetoxymethyl)-6,7,8,9-tetrahydro-pyrido [1,2-a]indol- 10-yl]-4(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of a red solid of melting point 238°-241° C.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:18][CH:17]=2)[CH:9]=1)(C)(C)C.C(N(CC)CC)C.[C@@H:38]1(C(O)=O)[CH2:42][CH2:41][CH2:40][C@@H:39]1[C:43]([OH:45])=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CN(C=O)C>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:10]2[CH:9]=[C:8]([NH:7][C:6]([C@H:38]3[CH2:42][CH2:41][CH2:40][C@H:39]3[C:43]([OH:45])=[O:44])=[O:5])[CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Reactant: O=C(O)[C@H]1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1)[C@H]1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
[3-(2′,4′-Difluoro-biphenyl-4-yloxymethyl)-phenyl]-carbamic acid tert-butyl ester (111 mg, 0.269 mmol) was stirred in 5 mL EtOAc (saturated with HCl) at RT for 45 min. The mixture was evaporated, re-evaporated from EtOAc and pumped under high vacuum to give a solid. The crude product was dissolved in DMF (2 mL). To this solution, chilled in an ice bath, was added triethylamine (150 uL, 1.08 mmol), (cis)-cyclopentane-1,2-dicarboxylic acid (64 mg, 0.404 mmol) and HATU (154, 0.404 mmol) was added and then let stir at RT for 30 min. The reaction mixture was diluted with EtOAc (25 mL), washed with 1N HCl (10 mL), H2O (10 mL), saturated NaCl (10 mL), dried over MgSO4, filtered and evaporated to give a white solid. The crude product was purified by flash chromatography with a 0-55% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in hexanes to yield 64.8 mg of rac-(cis)-2-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-phenylcarbamoyl]-cyclopentanecarboxylic acid as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:34]=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][N:23]4[N:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:34]=[C:22]4[N:21]=3)=[CH:18][CH:19]=2)[CH2:11][C:10]([CH3:12])([OH:13])[CH2:9]1
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(-c3nc4nc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CC(N)(c2ccc(-c3nc4nc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 7-1 (54 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 7-2.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[S:9][C:10]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=C(C(O)=O)[N:12]=1>ClCCl.CN(C)C=O>[Cl:7][C:8]1[S:9][C:10]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[C:1]([C:2]([Cl:4])=[O:3])[N:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc(Cl)sc1CCc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc(Cl)sc1CCc1cccc(Cl)c1

Procedure:
Oxalyl chloride (1.75 ml) was added to a solution of the product from step (iii) (3.14 g) in dichloromethane (30 ml) at room temperature containing 2 drops of dimethylformamide. After 4 h the volatiles were removed under reduced pressure to leave the subtitle product. Used directly in the next step.
Reaction SMILES: [Br-:1].[Li+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@@H:19](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:20][O:21][C@H:15]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1>CS(C)=O.O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C@H:14]2[CH2:18][O:17][C@@H:16]3[C@@H:19]([Br:1])[CH2:20][O:21][C@H:15]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 110 °C
Reaction time: 1.75 h
Yield: 54.6 %

Procedure:
Lithium bromide (19.2 g, 220.2 mmol) was added to a stirred solution of ditosylate (42) (40.0 g, 88.1 mmol) in dimethyl sulfoxide (200 mL) under an atmosphere of argon. The mixture was heated at 110° C. for 8 hours then at 120° C. for 1.75 hours. The mixture was diluted with water (500 mL) then extracted with tert-butyl methyl ether (4×250 mL). The organic phase was washed with water (3×250 mL) then brine (250 mL), dried (MgSO4), filtered and reduced in vacuo to leave an orange solid. Recrystallisation from methanol (100 mL) gave bromotosylate (47) (17.47 g, 55%) as a pale yellow solid. [□]D15+49.5° (c=11.7, CHCl3).
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH3:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([NH:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=1)=[O:38].FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][N:41]=4)=[O:38])=[C:21]([CH3:20])[CH:26]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)Nc1cc(C(F)(F)F)ccn1
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1cc(-c2c(C)c(CN3CCOCC3)n3ncnc(N)c23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccn1
Yield: 36 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using 5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAI (1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)-pyridin-2-yl]urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) 59 mg (36%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 10.19 (s, 1H), 9.52 (br s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.23 (s, 1H), 7.18 (dd, J=2.1, 8.7 Hz, 1H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.42-2.40 (m, 4H), 2.35 (s, 3H), 2.09 (s, 3H); MS [M+H]+=541.1; LCMS RT=2.49.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][O:20][C:21]2=[O:26]>ClCCl>[CH:1](=[N:16]/[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][O:20][C:21]2=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 95 %

Procedure:
To a stirred mixture of benzaldehyde (1.91 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (100 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (3.38 g, yield 95%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.41 (s, 2H), 7.36-7.37 (d, J=7.6 Hz, 1 H), 7.49-7.59 (m, 4H), 7.77-7.78 (d, J=7.6 Hz, 1 H), 7.92-7.94 (d, J=8.0 Hz, 2H), 8.55 (s, 1H), LC-MS (ESI) m/z: 238 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(Br)c1ccccc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(C(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (2.73 g), (1-bromoethyl)benzene (1.15 mL) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 19%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:60](O)(=[O:62])[CH3:61]>CN(C=O)C.O>[C:60]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH3:30])[C:9]2[C:10]([CH3:29])=[C:11]([CH:25]=[C:26]([Br:28])[CH:27]=2)[C:12]([NH:14][CH2:15][C:16]2[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[O:13])[CH2:6][CH2:7]1)(=[O:62])[CH3:61]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)[C@H]3CC[C@@H](N)CC3)c2C)c(=O)[nH]1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@H]1CC[C@@H](N(C)c2cc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c2C)CC1
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a stirred solution of compound cis-3-((4-aminocyclohexyl)(methyl)amino)-5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (free base) (0.225, 0.474 mmol) in DMF (3 mL), EDCI.HCl (0.138 g, 0.718 mmol), HOBt (0.064 g, 0.47 mmol), triethyl amine (0.1 g, 0.99 mmol) and acetic acid (0.057 g, 0.949 mmol) were added at room temperature and stirred at same temperature for 18 h. On completion, water was added and extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated giving crude material; which then purified by column chromatography to afford the desired compound (0.17 g, 72%). LCMS: 517.25 (M+1)+; HPLC % 95.83 (@ 254 nm) (Rt; 4.894; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.22 (t, 1H), 7.76 (d, 1H, J=7.2 Hz), 7.23 (s, 1H), 7.03 (s, 1H), 5.85 (s, 1H), 4.23 (d, 2H, J=3.6 Hz), 3.71 (bs, 1H), 2.89 (m, 1H), 2.53 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.81 (s, 3H), 1.74-1.76 (m, 2H), 1.53 (m, 2H), 1.39 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:6][CH:7]([CH3:9])C)[CH2:4][SH:5].[CH2:12](C(C(OCC)=O)C(OCC)=O)CCC>>[OH:11][CH2:10][C:3]([CH2:2][OH:1])([CH2:6][CH2:7][CH2:9][CH3:12])[CH2:4][SH:5]
Reactant: CC(C)CC(CO)(CO)CS
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Product: CCCCC(CO)(CO)CS

Procedure:
2,2-di-hydroxymethyl-hexan-1-thiol was prepared in an analogous manner to 2,2-di-hydroxymethyl-4-methyl-pentan-1-thiol starting from diethyl n-butylmalonate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].[NH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.C(N(C(C)C)CC)(C)C.Cl.[F:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH:34]2[CH2:37][NH:36][CH2:35]2)=[CH:31][CH:30]=1>C(#N)C>[F:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH:34]2[CH2:35][N:36]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([N:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11][CH2:10][CH2:9]3)=[O:7])[CH2:37]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: O=C=NCCCBr
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCN1CC(Oc2ccc(F)cc2)C1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-Bromo-3-isocyanato-propane (0.164 g, 1.0 mmol) in acetonitrile is stirred with 1,2,3,4-Tetrahydro-quinoline (0.133 g, 1.0 mmol) and diisopropylethylamine (0.2 ml, 1.2 mmol). The reaction mixture is stirred for 2 hours at ambient temperature and then the solvent removed. The crude product is taken-up in acetonitrile (4 ml) and diisopropylethylamine (0.2 ml, 1.2 mmol) and 3-(4-Fluoro-phenoxy)-azetidine hydrochloride (0.11 g, 1.0 mmol) added. The reaction mixture is stirred at ambient temperature for 18 hours, the solvent evaporated and the crude partitioned between ethylacetate and saturated sodium bicarbonate solution. The organic phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (elution gradient ethylacetate then 5:95 methanol/dichloromethane) to afford 3,4-Dihydro-2H-quinoline-1-carboxylic acid {3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-amide. [MH]+ 444.2
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19]>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: OCCBr
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CCO)CC1
Yield: 78 %

Procedure:
In an atmosphere of argon, 4-(4-fluorobenzoyl)piperidine (2.07 g, 10 mmol) was dissolved in triethylamine (30 ml) to which was subsequently added dropwise 2-bromoethanol (1.1 ml, 14.7 mmol) at room temperature. After 1 hour of heating under reflux, triethylamine was removed by evaporation, and the resulting residue was mixed with saturated sodium carbonate aqueous solution (40 ml) and extracted with ethyl acetate. The resulting organic layer was dried on anhydrous sodium carbonate, the solvent was removed by evaporation and then the resulting residue was purified by subjecting it to a silica gel column chromatography (ethyl acetate-methylene chloride:methanol=10:1) to obtain 1.96 g (78.0%) of the title compound in the form of light yellow solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(C(O)c2ccc(F)cc2)cc1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C#N)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 961 mg (4.23 mmol) of the compound from Example 173A in analogy to the synthesis of the compound from Example 278. 276 mg (17% of theory) of the target compound were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C.C(Cl)Cl>[CH2:19]([O:18][C:16]([C:12]1([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:15][CH2:14][CH2:13]1)=[O:17])[CH3:20]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)C1(Br)CCC1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(Nc2ccc3[nH]ncc3c2)CCC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 17.3 %

Procedure:
A mixture of 1H-indazol-5-ylamine (5.0 g, 37.6 mmol), ethyl 1-bromocyclobutane carboxylate (7.78 g, 6.08 mL, 37.6 mmol) and triethylamine (7.60 g, 10.5 mL, 75.1 mmol) in ethanol (5 mL) was heated at 100° C. for 3 days, then at 140° C. for 2 days. The reaction mixture was cooled to ambient temperature, and after 7 days the mixture was diluted with DCM (50 mL) and filtered. The filtrate was concentrated in vacuo then purified by chromatography (silica, 2 to 10% of a 9:1 MeOH:NH4OH solution in DCM) to give 1-(1H-indazol-5-ylamino)-cyclobutanecarboxylic acid ethyl ester (1.68 g, 6.49 mmol, 17%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([CH:10]([CH3:12])[CH3:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:12])[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)c1cccc(N)c1
Product: CC(C)c1cccc(Nc2ncc(F)c(Nc3cccc(C(C)C)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-isopropylaniline were reacted to give N2,N4-bis-(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret time: 29.58 min.; Purity: 98%; MS (m/e): 365 (MH+); 1H NMR (DMSO-d6): δ 10.5 (1H, s), 10.34 (1H, s), 8.41 (1H, d, J=5.1 Hz), 7.62 (1H, d, J=8.1 Hz), 7.53 (1H, s), 7.43 (1H, d, J=8.1 Hz), 7.37 (2H, m), 7.29 (1H, t, J=8.1 Hz), 7.19 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz), 2.88 (2H, m), 1.25 (6H, d, J=7.2 Hz), 1.201 (6H, d, J=7.2 Hz).