Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:12]Br.O>C(O)C>[Br:12][CH2:2][C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)C1(C(C)=O)CC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)CBr)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Ethyl 1-acetylcyclopropanecarboxylate (200 g, 1.28 mol) was dissolved in ethanol (1000 ml), and bromine (72.7 ml, 1.41 mol) was added dropwise while stirring and cooling with ice. After completion of dripping, the temperature of the reaction solution was raised to 30° C. and stirring was performed for 2 hours. After adding water (1000 ml) to the reaction solution while cooling with ice, it was concentrated under a reduced pressure was performed. After extracting the concentrate into ethyl acetate (750 ml×2), it was washed with a 10% aqueous sodium thiosulfate solution (500 ml×2) and saturated sodium bicarbonate water (500 ml×2) in that order and then dried over anhydrous sodium sulfate. After filtering and concentrating the filtrate under a reduced pressure, 291 g (97%) of the title compound was obtained as a yellow, oily substance.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[CH:1]1([CH2:4][NH:5][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 15.1 g (0.22 mol) cyclopropylmethylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 17 grams of diketene (0.20 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 19.7 g (0.13 mol, 63% yield) of a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][CH3:12])=[N:5][NH:6]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC(OC)=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][CH3:12])=[N:5][NH:6]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Reactant: COc1n[nH]c2cccc(Br)c12
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]nc(OC)c12

Procedure:
3-(3-Methoxy-1H-indazol-4-yl)-3-phenyl-acrylic acid ethyl ester CLXXXVII was prepared from 4-bromo-3-methoxy-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[SH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>C(#N)C>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([S:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: CC#N
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Sc3ccc(C(=O)O)cc3)ncc21
Yield: 26.8 %

Procedure:
A solution of 2-Chloro-9-cyclopentyl-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.324 mmol) and 4-mercaptobenzoic acid (50 mg, 0.324 mmol) in acetonitrile (5 mL) was heated under reflux for 4 hours. Additional 4-mercaptobenzoic acid (50 mg, 0.324 mmol) was added and the reaction mixture was heated under reflux for 16 hours. After cooling, the crude reaction mixture was filtered through Celite and washed with acetonitrile. The crude product was purified by column chromatography (0%-10% MeOH: CH2Cl2) and triturated with MeOH to give the title compound (37 mg, 27% yield) as a white solid. NMR DMSO D6 1.03 (6H, s), 1.20-1.38 (6H, m), 1.42-1.53 (2H, m), 3.17 (3H, s), 3.27 (2H, s), 4.47 (1H, dt), 7.72 (2H, dd), 7.99 (2H, dd), 8.02 (1H, s); MS (ES+) 427, (ES−) 425.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[Br:30][C:31]1[CH:32]=[CH:33][C:34]([NH2:45])=[N:35][C:36]=1[C:37]#[C:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH:3]([CH3:7])[C:4]([NH:45][C:34]1[CH:33]=[CH:32][C:31]([Br:30])=[C:36]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:35]=1)=[O:6])[CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccc(Br)c(C#Cc2ccccc2)n1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (36 g, 177 mmol) and N,N′-dicyclohexylcarbodiimide (22.5 g, 109 mmol) in DCM (150 ml) is stirred with ice bath cooling for 30 minutes. A solution of 5-bromo-6-(2-phenylethynyl)pyridin-2-amine B2a (20 g, 73.2 mmol) in DCM (100 ml) is added. After stirring for 7 days at RT the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 25 g (74%). HPLC-MS: M+H=458/460; tR=2.33 min (*Method—1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13]COC)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[CH:23]=CC=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1.C(C1[S:31]C=C(C(O)=O)N=1)(C)C.NC1C(Cl)=C(OC)C=CC=1C(=O)C>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[N:19]=[C:20]([CH:24]([CH3:26])[CH3:25])[S:31][CH:23]=2)[CH:3]=1
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Agent: COc1ccc(C(C)=O)c(N)c1Cl
Product: COc1ccc2c(Cl)cc(-c3csc(C(C)C)n3)nc2c1Cl

Procedure:
4,8-Dichloro-2-(2-isopropyl-thiazol-4-yl)-7-methoxy-quinoline was prepared in a similar fashion as 4,8-dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline except that 2-isopropyl-thiazole-4-carboxylic acid was used instead of 6-isopropyl-pyridine-2-carboxylic acid and 1-(2-Amino-3-chloro-4-methoxy-phenyl)-ethanone was used instead of 1-[2-amino-3-chloro-4-(2-methoxy-ethoxy)-phenyl]-ethanone
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[S:14](F)(=[O:16])=[O:15])[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7]2)[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[S:14]([C:28]1[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=1)(=[O:15])=[O:16])[CH2:10][NH:9][CH2:8][CH2:7]2)[CH3:2]
Reactant: CCOc1cc2c(cc1S(=O)(=O)F)CN(C(=O)C(F)(F)F)CC2
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice bath cooled solution of 6-ethoxy-2-(2,2,2-trifluoro-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl fluoride (1.30 g, 3.66 mmol) in THF (13 mL) was added dropwise 4-fluorophenylmagnesium bromide (18.3 mL, 18.3 mmol). The mixture was stirred at room temperature overnight before quenching with aqueous sodium potassium tartrate tetrahydrate (13 g). The aqueous was extracted twice with diethyl ether. The organics were combined, dried and evaporated to dryness. The resulting oil was purified by chromatography on silica, eluting with 1 to 10% MeOH/NH3 in dichloromethane to yield the title compound D31 as a solid (700 mg). MH+ 336. 1H NMR δ (CDCl3)1.22-1.37 (3H, t), 2.74-2.91 (2H, m), 3.08-3.19 (2H, t), 4.01 (2H, s), 4.13-4.25 (2H, m), 6.58 (1H, s), 7.06-7.20 (2H, m), 7.83 (1H, s), 7.91-8.01 (2H, m).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].ClCC1N(C)[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2N=1.[CH3:28]N(C)C=O>>[CH3:28][C:12]1[N:13]=[C:8]([N:7]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:21]=2)[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: CN(C)C=O
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(N(c2ccccc2)c2ccccn2)n1

Procedure:
To a flask were added 1.1 g of 2,2′-dipyridylamine and 25 ml of N,N-dimethylformamide. To this mixture were added 0.32 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 10 C for ten minutes, 1.2 g of 2-(chloromethyl)-1-methyl-1H-benzimidazole in 5 ml of N,N-dimethylformamide were added. The reaction mixture was stirred at 22 C for several hours, and then quenched with 40 ml water. The product was extracted with 50 ml ethyl acetate, and then extracted with 30 ml of 1M hydrochloric acid, and basified with 3M sodium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using 33% ethyl acetate, 62% hexane, and 5% methanol, resulting in an oil which crystallized on standing. After drying, 0.6 g of a yellow solid remained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([CH3:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:33])[C:9](=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]2)[C@@H:10]([CH3:31])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:36])[CH3:35]
Reactant: CC(C)CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)CC(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Analogously to Example 2c, 1.5 g of 11β,21-dihydroxy-17-isovaleryloxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted in 15 ml of pyridine with 7.5 ml of acetic anhydride, worked up, and purified, thus isolating 980 mg of 21-acetoxy-11β-hydroxy-6α-methyl-17-isovaleryloxy-1,4-pregnadiene-3,20-dione, mp 172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[OH2:19].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[C:31]2[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]2=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1.[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[C:31]2[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]2=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(F)cc2F)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(F)cc2F)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.8 g of ethyl 2-[3-(2,4-difluorophenyl)ureido]thiazol-4-ylglyoxylate, 0.96 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 30 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:39])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][C@H:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:31][O:32]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:39])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][C@H:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:31][OH:32])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:40][CH:41]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)C[C@@H](O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)C[C@@H](O)c1ccco1

Procedure:
A solution of 121 mg of compound N-(4-chlorobenzyl)-2-{[[(2R)-2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 3 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 3% MeOH in CH2Cl2 provides 19 mg of the title compound as a brown solid. Recrystallization from EtOAc-hexane affords granular brown crystals.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[N+]([O-])=O.[CH3:17][OH:18]>[Pd]>[CH3:12][C:6]1([CH3:13])[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:17](=[O:18])[NH:8][C:7]1=[O:11]
Reactant: CO
Reactant: CC1(C)C(=O)Nc2cc(N)c([N+](=O)[O-])cc21
Agent: [Pd]
Product: CC1(C)C(=O)NC(=O)c2ccccc21

Procedure:
A solution of 18.7 g. (0.085 mol) 6-amino-3,3-dimethyl-5-nitroindolin-2-one in 200 ml. methanol is hydrogenated at 40° C. in the presence of 1.9 g. of 10% Pd/C. The catalyst is filtered off with suction, the filtrate is evaporated and the residue is crystallised from ethanol. Yield: 15.6 g. (96% of theory); m.p. 245°-247° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C@H:3]1[CH2:16][C@@H:15]([CH3:17])[O:14][CH:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:4]1[OH:18].[H-].[Na+].[CH3:22]OS(OC)(=O)=O>O1CCCC1.C(OCC)(=O)C.O>[CH3:22][O:18][C@@H:4]1[C@@H:3]([N:2]([CH3:1])[CH3:19])[CH2:16][C@@H:15]([CH3:17])[O:14][CH:5]1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: C[C@@H]1C[C@H](N(C)C)[C@@H](O)C(OCc2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CO[C@H]1C(OCc2ccccc2)O[C@H](C)C[C@@H]1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Benzyl 3,4,6-trideoxy-3-(dimethylamino)-D-xylohexopyranoside (Korte, F., A. Bilow and R. Heinz, Tetrahedron, 1962, 18, 657,666, 10.01 g, 38.06 mmoles) was dissolved in tetrahydrofuran (300 mL) with stirring at room temperature under an argon atmosphere. The solution was treated with small portions of sodium hydride (60% oil dispersion, 1.83 g, 45.68 mmoles). After one hour, dimethylsulfate (5.28 g, 41.87 mmoles) was added and the reaction mixture was stirred for two hours. The reaction mixture was quenched by the careful addition of water and the solution was evaporated in vacuo leaving an-oily residue which was resuspended in ethyl acetate and water. The organic layer was separated, dried (MgSO4) and filtered to afford 9.74 g (93%) of the title compound as a slightly yellow oil which solidified on standing.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C([N:21](CC)CC)C.NC[CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:21][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCN1CCOCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NCN3CCOCC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 4-(2-aminoethyl)morpholine (15 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:25][CH:24]=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=2)[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].Cl>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:25][CH:24]=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=2)[CH2:9][CH2:10][O:11][S:46]([CH3:45])(=[O:48])=[O:47])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CN(CCO)C(=O)OC(C)(C)C)[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(2-{[N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino]methyl}phenyl)-3-cyclohexyl-1H-indole-6-carboxylate (424 mg, 0.830 mmol) and triethylamine (0.14 ml, 1.0 mmol) in chloroform (5.0 ml) was added dropwise methanesulfonyl chloride (0.07 ml, 0.90 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-(2-{[N-tert-butoxycarbonyl-N-(2-methanesulfonyloxyethyl)amino]methyl}phenyl)-3-cyclohexyl-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 5 without purification.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=3)[NH2:27])[CH2:18][CH2:17]2)[N:7]=1.[F:31][C:32]1[C:37]2[C:38](=O)[O:39][CH2:40][C:36]=2[CH:35]=[CH:34][CH:33]=1.S(Cl)([Cl:44])=O>ClCCl>[Cl:44][CH2:40][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[C:37]=1[C:38]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[C:24]([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][N:16]([C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:13]=3[CH:14]=[CH:15][C:6]([CH3:5])=[N:7]4)[CH2:21][CH2:20]2)[CH:25]=1)=[O:39]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1OCc2cccc(F)c21
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5c(F)cccc5CCl)c4)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of trimethylaluminum (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem. Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude 2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in DCM and to 0° C. To the stirred solution was added dropwise thionyl chloride (1 eq.). The reaction mixture was warmed to room temperature, stirred for 1 hour then partitioned between saturated aqueous sodium hydrogencarbonate solution and DCM. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude 2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide thus obtained was dissolved in methanol and cooled to 0° C. To the stirred solution was added sodium methoxide (1.2 eq.) portionwise. The solution was warmed to room temperature and stirred for 18 hours. The solution was concentrated and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SPE cartridge (Silica) eluting with DCM-methanol (96:4) affording the title compound (yield 24%).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:21]([C:22](O)=[O:23])[CH:20]=1.[BH4-].[Na+]>ClCCl.O>[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:20]=[C:21]([CH2:22][OH:23])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: COC(=O)c1cc(F)cc(C(=O)O)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
Triethylamine (2.2 ml, 16.0 mmol) and isobutyl chloroformate (1.0 ml, 8.0 mmol) were added to an ice-cooled solution of 5-fluoro-isophthalic acid monomethyl ester (1.3 g, 6.7 mmol) in dichloromethane (20 ml) and then warmed to room temperature. After stirring for 2 h, the reaction mixture was filtered and concentrated. The residue was re-dissolved tetrahydrofuran (10 ml) and then sodium borohydride (1.1 g, 29.02 mmol) in water (3ml) was added drop-wise. After 1 h, the reaction was quenched with methanol and then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Flash column chromatography on silica gel using 30% ethyl acetate in hexanes afforded 667 mg (54%) of 3-fluoro-5-hydroxymethyl-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3), δ (ppm): 7.82 (s, 1H), 7.63 (d, 1H), 7.32 (d, 1H), 4.76 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[Li]CCCC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[OH:8][C:9]1[C:10](=[O:15])[N:11]([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc(O)c2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
3-tert-Butyldimethylsilyloxy-1H-pyridin-2-one (1 eq.) (Posner et al. J. Org. Chem. 1992, 57, 4088.) is cooled down to −78° C., in THF (10 mL) and is treated with n-BuLi (1.6 M soln. in hexane, 1.1 eq.). The solution is stirred for 20 min at −78° C., followed by the addition of p-toluenesulfonyl chloride (1.1 eq.). The solution is allowed to warm up to room temperature over one hr, quenched with water (10 mL), extracted with EtOAc (3×), washed with brine (1×), dried (Na2SO4) and concentrated. The residue is taken up in ethanol (10 mL) and treated with conc. HCl (2 mL). The mixture is allowed to stir for 1 h, the solvent is removed to obtain the desired compound as a white solid.