Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]4[F:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:40]=O>>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:40])[CH2:24][C@H:23]4[F:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: C=O
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 274) and formaldehyde following General Procedure R.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH:9]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1-(3-chlorophenyl)ethanone (1.54 g, 10 mmol), 4-chlorobenzaldehyde (1.4 g, 10 mmol) in EtOH (25 mL) was added aq. KOH (50% wt, 10 mmol, 0.56 mL). The reaction was stirred at RT for 2 h then filtered the insoluble white solid. The solid was dried and washed with PE/EA (5:1, 10 mL) to give 1-(3-chlorophenyl)-3-(4-chlorophenyl)prop-2-en-1-one (2.3 g, 83% yield) as a white solid. LCMS: MH+ 277 and TR=2.050 min. Used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(NS(C)(=O)=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(NS(C)(=O)=O)CC1
Temperature: 65 °C

Procedure:
A mixture of N-[1-(7-acetyl-5-chloroquinolin-8-yl)piperidin-4-yl]methanesulfonamide (0.027 g, 0.071 mmol) and ammonium acetate (0.0545 g, 0.707 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.17 mL, 0.17 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H24ClN4O2S (M+H)+: m/z=383.1; Found: 383.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][O:11][CH:12]2[C:23]3[C:24](=[O:25])[C:19]([O:26][Si](C(C)(C)C)(C)C)([CH2:20][CH2:21][CH:22]=3)[C:18]#[C:17][CH:16]=[CH:15][C:14]#[C:13]2)=[CH:8][CH:7]=1)=[O:4].FC(F)(F)S(O)(=O)=O>CCOCC.C(OCC)(=O)C>[OH:26][C:19]12[C:24](=[O:25])[C:23](=[CH:22][CH2:21][CH2:20]1)[CH:12]([O:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:35][CH:34]=1)[C:13]#[C:14][CH:15]=[CH:16][C:17]#[C:18]2
Reactant: COC(=O)Cc1ccc(COC2C#CC=CC#CC3(O[Si](C)(C)C(C)(C)C)CCC=C2C3=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(COC2C#CC=CC#CC3(O)CCC=C2C3=O)cc1
Yield: 60 %

Procedure:
The silyl ether (8a) was dissolved in 4 mL of anhydrous ether and treated with 100 mL of trifluoromethanesulfonic acid, diluted with ethyl acetate and washed with saturated bicarbonate. The organic fraction was dried over MgSO4 and the residue combined with compound 8b obtained above and chromatographed over silica gel (2:1 hexane/ethyl acetate) to give 50 mg (60%) of compound 8b as a colorless oil:
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[N:38]1[CH:39]=[CH:40][CH:41]=[N:42][C:37]=1[O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: Clc1ncccn1
Product: COc1cc2c(cc1OC)C(Cc1ccc(Oc3ncccn3)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 2-chloro-pyrimidine
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14])([O-:9])=[O:8]>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
N,N-Dimethylethylendiamine (14.25 g, 61.0 mmol) was added dropwise into a solution of commercially available 3-nitrobenzoyl chloride (25.0 g, 134 mmol) in dry THF (150 mL) at 0° C. and stirred for 45 min. The reaction mixture was evaporated to under reduce pressure to dryness and residue was recrystallized from EtOH to give N-(2-dimethylaminoethyl)-3-nitrobenzamide; 31.0 g (97%); mp 89-90° C.; 1H NMR (CDCl3) δ 2.29 (6H, s, 2×Me), 2.57 (2H, t, J=5.8 Hz, CH2), 3.57 (2H, q, J=5.6 and 5.8 Hz, CH2), 7.37 (1H, brs, exchangeable, NH), 7.63 (H, d, J=7.9 Hz, ArH) 8.19 (1H, m, ArH), 8.33 (1H, m, ArH), 8.66 (1H, s, ArH). Anal. Calcd. for (C13H21N3O3): C, 58.41, H, 7.92, N, 15.72. Found: C, 58.23, H, 7.69, N, 15.90.
Reaction SMILES: [O:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N:10]1[C:17]2[N:13]([N:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[CH:12]=[CH:11]1)[CH3:2].[F:24][S:25]([F:38])([F:37])([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[CH3:2][O:1][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([S:25]([F:38])([F:24])([F:35])([F:36])[F:37])[CH:27]=2)=[CH:5][C:4]=1[N:10]1[C:17]2[N:13]([N:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[CH:12]=[CH:11]1
Reactant: COc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Product: COc1ccc(NC(=O)c2cccc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
45 mg (0.15 mmol) of the compound of Example 10A and 37 mg (0.15 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid were reacted and worked up analogously to the procedure of Example 16. This gave 72 mg (91% of theory) of the title compound.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.Cl>CC(C)=O>[F:12][C:11]([F:13])([F:14])[C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH:3]=[O:2])=[CH:10][CH:9]=1
Reactant: COC=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(C)=O
Product: O=CCc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a solution of 1-(2-methoxy-vinyl)-4-trifluoromethylbenzene (10.5 g, 0.052 mol, from step (i) above) in 158 ml acetone was added 107.3 ml 3 M HCl and stirred at 45° C. for 4 h. Acetone was evaporated under reduced pressure and the residue was partitioned between water and ether. Organic layer was washed with NaHCO3, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title compound (9.4 g ) as pale yellow liquid. This was directly taken for next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:28][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][N:22]3[CH3:21])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CN1CCCCC1CCl
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCCC1COc1ccc2nc(C#N)nc(NCC(C)(C)C)c2c1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.3 1 mmol), 1-methyl-2-chloromethyl-piperidine hydrochloride (0.41 mmol) and potassium carbonate (7.2 mmol) are stirred in DMF (3 ml) at 80° C. for 8 hours. The solvent is evaporated, the residue is dissolved in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=9:1) as mobile phase. The product containing fractions are combined and evaporated. A pale oil with Rf=0.54 (CH2Cl2/MeOH=10:1) is obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[O:27])=[CH:21][CH:20]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (30.0 mg, 0.128 mmol) prepared in Process 3 of Example 12 in dichloromethane (3 mL) was added sequentially with 4-chlorophenyl isocyanate (19.7 mg, 0.128 mmol), triethylamine (19.4 mg, 0.192 mmol), DMAP (catalyst amount) at room temperature, and the resultant was stirred at the same temperature for 1.5 hours. The reaction solution was filtered using celite, concentrated in vacuo, and the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (49.7 mg, 100%) was obtained as a white crystalline powder.
Reaction SMILES: CN([C:7]1[CH:8]=[C:9]([CH:22]=[C:23](Br)[CH:24]=1)[C:10]([NH:12][C@@H](C1C=CC(F)=CC=1)C)=[O:11])S(C)(=O)=O.CC(C)=O.C(NC(C)C)(C)C.C[Si](C#C)(C)C>CCOC(C)=O.[Cu]I.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCOCC1>[C:10]([NH2:12])(=[O:11])[C:9]1[CH:22]=[CH:23][CH:24]=[CH:7][CH:8]=1
Reactant: C[C@@H](NC(=O)c1cc(Br)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: C#C[Si](C)(C)C
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(N-methyl-N-(methylsulfonyl)amino)-5-bromo-N—((R)-1-(4-fluorophenyl)ethyl)benzamide (200 mg, 0.46 mmol), copper(I)iodide (3.6 mg, 0.019 mmol), bis(tri-t-butylphosphine) palladium (0) (14 mg, 0.028 mmol) and tris(dibenzylide acetone) dipalladium (0) chloroform adduct (14.2 mg, 0.014 mmol) in 0.5 mL degassed dioxane was added diisopropylamine (0.084 mL, 0.60 mmol) and (trimethylsilyl)acetylene (0.085 mL, 0.60 mmol). The reaction was stirred at rt overnight and then heated to 60° C. for an additional night. The mixture was diluted with EtOAc and filtered through celite. Concentration and flash chromatography (10-50% EtOAc/hexanes) gave 3-(N-methyl-N-(methylsulfonyl)amino)-N—((R)-1-(4-fluorophenyl)ethyl)-5-(2-trimethylsilyl)ethynyl)benzamide. 1H NMR (CDCl3) δ 7.77 (m, 1H), 7.67 (m, 1H), 7.61 (m, 1H), 7.35 (m, 2H), 7.05 (m, 2H), 6.28 (d, J=7.3 Hz, 1H), 5.29 (m, 1H), 3.33 (s, 3H), 2.86 (s, 3H), 1.60 (d, J=7.0 Hz, 3H), 0.26 (s, 9H).
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:68]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH2:65][CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][N:69]([C:73]([O:75][CH2:76][C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)=[O:74])[CH2:68]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 3-(4-bromobutyl)-1-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[F:19][C:20]([F:34])=[CH:21][CH2:22][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][OH:25].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([O:25][CH2:24][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:21]=[C:20]([F:34])[F:19])[CH:3]=[CH:4][C:5]2=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC=C(F)F
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC=C(F)F)NC(=O)OC(C)(C)C)ccc21
Temperature: 90 °C
Yield: 46.3 %

Procedure:
A suspension of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.26 g, 4.88 mmol), prepared as in Example 16, Part G, (S)-tert-butyl (5,5-difluoro-1-hydroxypent-4-en-2-yl)carbamate (1.39 g, 5.86 mmol), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.42 g, 0.98 mmol), Pd(OAc)2 (0.11 g, 0.49 mmol), Cs2CO3 (3.18 g, 9.76 mmol), and anhydrous toluene (15 mL) was purged with nitrogen for 10 minutes and heated to 90° C. overnight (15 h). After cooling, the reaction mixture was filtered through diatomaceous earth (Celite®), concentrated under reduced pressure and dissolved in ethyl acetate (50 mL). The organic layer was washed with brine (1×100 mL) and water (1×100 mL); dried over Na2SO4 and concentrated under reduced pressure to afford an amber oil. The crude material was purified over SiO2 (1-5% 2M ammonia in methanol/dichloromethane gradient elution) to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-5,5-difluoropent-4-en-2-yl)carbamate (1.04 g, 2.26 mmol, 46% yield) as a tan solid. LC/MS, (ESI) m/z 460.0 [(M+H)+, calcd for C24H28F2N3O4, 460.2]; 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (d, J=5.5 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.73 (d, J=5.8 Hz, 1H), 6.83 (dd, J=8.8, 1.8 Hz, 1H), 6.79 (br. s., 1H), 5.13-4.89 (m, 1H), 4.39-4.21 (m, 1H), 4.20-3.96 (m, 3H), 3.66 (s, 3H), 3.12 (s, 3H), 2.61-2.31 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:26][N:27]([CH3:29])[NH2:28]>>[CH3:26][N:27]([CH3:29])[NH:28][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Reactant: CN(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NN(C)C)n(C)n1
Yield: 94 %

Procedure:
As described for example 81c, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (73 mg, 0.21 mmol) was converted, using N,N-dimethylhydrazine instead of morpholine, to the title compound (74 mg, 94%) which was obtained as a colorless oil. MS: m/e=375.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(Cc3ccccc3)c3ccccc23)cc(OC)c1OC
Yield: 70.3 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (2.37 g) obtained in Example 1 and benzyl bromide (1.8 g) except that the obtained crude crystals were recrystallized from ethanol and then from a mixed solvent of ethyl acetate and hexane, to give Compound 47 (2.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH2:19])=[CH:7]2.CCN(C(C)C)C(C)C.[Cl:29][C:30]1[C:35]([O:36][CH3:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1>C(O)CCC>[Cl:29][C:30]1[N:31]=[CH:32][N:33]=[C:34]([NH:19][CH2:18][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:35]=1[O:36][CH3:37]
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1
Reactant: COc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1c(Cl)ncnc1NCc1cc2cccc(Cl)c2nc1-c1ccccc1

Procedure:
A mixture of (8-chloro-2-phenylquinolin-3-yl)methanamine (0.035 g, 0.13 mmol) in n-butanol (3 mL) was treated with DIEA (0.046 mL, 0.26 mmol, 2.0 eq) followed with 4,6-dichloro-5-methoxypyrimidine (0.025 g, 0.14 mmol, 1 eq) at 100° C. for 8 h. The reaction mixture was concentrated and purified by column chromatography on a Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to provide 6-chloro-N-((8-chloro-2-phenylquinolin-3-yl)methyl)-5-methoxypyrimidin-4-amine as a white solid. 1H-NMR (DMSO-d6) δ ppm 8.33 (s, 1H), 8.20 (t, 1H), 8.02-8.04 (m, 1H), 7.99 (s, 1H), 7.93-7.95 (m, 1H), 7.70 (d, J=6.60, 1H), 7.46-7.61 (m, 1H), 4.73 (d, J=5.71, 2H), 2.51 (s, 3H), Mass Spectrum (ESI) m/e=412 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Cc1ccc(OCCCBr)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-hydroxyphenyl)propan-2-one (1 g, 6.67 mmol), 1,3-dibromopropane (0.74 mL, 7.3 mmol) and potassium carbonate (1.84 g, 13 3 mmol) in 2-butanone (30 mL) was heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with additional ethyl acetate. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 10% ethyl acetate/hexanes to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 2.14 (s, 3H), 2.36-2.27 (m, 2H), 3.60 (t, J=6.4 Hz, 2H), 3.63 (s, 2H), 4.09 (t, J=5.8 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H); MS (DCI/NH3) m/z 288 (M+NH4)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:13][N:14]([CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN(C)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of methyl 4-formylbenzoate (1 g, 6.1 mmol) and N-methylbenzenamine (650 mg, 6.1 mmol) in methanol (50 mL) was added acetic acid (2 drops) and the mixture was stirred for 0.5 hour. Then sodium cyanoborohydride (660 mg, 10 mmol) was added in portions. The mixture was stirred at room temperature for 24 hours. The mixture was washed with water (50 mL) and extracted with dichloromethane (50 mL). The organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give methyl 4-((methyl(phenyl)amino)methyl)benzoate (400 mg, 26%) as a yellow oil. LRMS (M+H+) m/z: calcd 255.13. found 255. 1H NMR (300 MHz, CD3OD): δ 7.96-7.32 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.18-7.12 (m, 2H), 6.74-6.60 (m, 3H), 4.60 (s, 2H), 3.88 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]([C:8]1[CH:32]=[CH:31][C:11]2[N:12]([CH3:30])[C:13]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7].[Li+].[OH-]>>[CH3:30][N:12]1[C:11]2[CH:31]=[CH:32][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:33])=[O:2])=[O:7])=[CH:9][C:10]=2[N:14]=[C:13]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Yield: 90.6 %

Procedure:
{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (211 mg) was prepared by following General Procedure E starting from {[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid methyl ester (240 mg), and LiOH (1.0 ml, 2.0 N solution in water). LC/MS: m/z 467.