Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]([OH:40])([C:27]([S:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)([CH3:29])[CH3:28])[CH2:25][OH:26].[C:41]1([C@H:47]([CH3:51])[C:48](O)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(OCC)(=O)C>ClCCl>[C:41]1([C@H:47]([CH3:51])[C:48]([O:26][CH2:25][C:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])([OH:40])[C:27]([S:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)([CH3:29])[CH3:28])=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C(O)(COC(=O)[C@@H](C)c2ccccc2)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 11.7 g (56.7 mmol) of 1,3-dicyclohexylcarbodiimide in 38 ml of dichloromethane was added dropwise to a mixture of 14.0 g (38.0 mmol) of (±)-2-(2,4-difluorophenyl)-3-((4-methoxyphenyl)methylthio)-3-methylbutane-1,2-diol, 6.3 g (41.8 mmol of (S)-(+)-2-phenylpropionic acid, 0.47 g (3.8 mmol) of 4-dimethyl-aminopyridine, and 190 ml of dichloromethane with stirring under ice-cooling, followed by stirring for 3 hours. The mixture was warmed to room temperature, and the stirring was continued for 12 hours. Ethyl acetate was added to the reaction mixture, and the precipitated insoluble matter was removed by filtration. The filtrate was washed successively with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of hexane and ethyl acetate (10:1) as an eluent. The solvent was removed from each fraction by distillation under reduced pressure to obtain diastereomers (A-1) and (A-2) of 2-(2,4-difluoro-phenyl)-2-hydroxy-3-((4-methoxyphenyl)methylthio)-3-methylbutyl (S)-(+)-2-phenylpropionate in a yield of 9.3 g (49%) and 8.7 g (46%), respectively, as a colorless oily substance.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].Br[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 78.6 %

Procedure:
To a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (300 mg, 0.593 mmol) in dry DMF (6 mL), was added (2-bromoethoxy)(tert-butyl)dimethylsilane (423 mg, 1.78 mmol) and cesium carbonate (578 mg, 1.78 mmol). The reaction mixture was stirred at r.t. for 36 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (3×10 mL). The organic layer was dried over anhydrous Na2SO4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Ethyl acetate:Pet. Ether) to afford title compound (310 mg, 78.8%) as white solid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:2]=1.[Na+:32].[Na+].Cl.CC[OH:37]>O>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([N:16]=[C:17]([NH2:19])[NH:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[OH2:37].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[Na+:32].[Na+:32]
Reactant: CCO
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
Pemetrexed Disodium Heptahydrate was prepared by adjustment of the pH of the Pemetrexed Disodium solution after saponification from pH=13 to pH=8 using HCl followed by addition of EtOH (3 times the volume of water) to achieve crystallization. Precipitated Pemetrexed Disodium Heptahydrate was isolated by filtration, washed with a mixture of EtOH and water (4:1 v/v) followed by EtOH. The wet product was dried in vacuo at 200 mbar at 20° C. to 30° C. until water content of the dried product was 20.1% to 22.1%.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3C=CC=[CH:17][CH:16]=3)[C:10](=[O:21])C(C#N)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:25]([OH:28])(=[O:27])[CH3:26]>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:21])[C:26]([C:25]([OH:28])=[O:27])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1nn(-c2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reactant: CC(=O)O
Agent: Cl
Product: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Temperature: 120 °C
Yield: 55 %

Procedure:
Intermediate j (9.2 g, 0.035 mol) was added to a mixed solvent of glacial acetic acid (100 mL) and HCl (72 mL, 0.86 mol). The mixture was warmed up to 120° C. and reacted under reflux for 4 h. The solvent was evaporated off. To the obtained fraction was added water (200 mL). The mixture was filtered by suction and dried to produce Intermediate g (6.5 g) in a yield of 55%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([NH:29][C@H:30]([CH:34]([CH3:36])[CH3:35])[C:31]([OH:33])=O)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[N:17][CH:18]=1.C[Si](C)(C)[NH:39][O:40][Si](C)(C)C>C(Cl)Cl>[OH:40][NH:39][C:31](=[O:33])[C@H:30]([NH:29][S:26]([N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][N:17]=2)[CH2:25][CH2:24]1)(=[O:28])=[O:27])[CH:34]([CH3:35])[CH3:36]
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Reactant: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Oxalyl chloride (0.58 ml, 6.7 mmol) and DMF (few drops) were added to a solution of (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1sulfonyl)amino}-3-methylbutyric acid (1.05 g, 2.7 mmol), [prepared as described in Step 1 above], in methylene chloride (85 ml) and the reaction mixture was stirred overnight at RT. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) and N,O-bis-trimethylsilylhydroxylamine (1.7 g, 9.4 mmol) was added. After 3 h, the reaction was concentrated, methanol (20 ml) was added and after stirring for an additional 30 min., the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. Chromatography (SiO2, 1-2% methanol/methylene chloride) gave N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl-oxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide as a white solid (35%), mp 97.0-98.4° C.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1.[Cl:35][C:36]1[N:41]=[C:40](Cl)[C:39]([F:43])=[CH:38][N:37]=1>>[Cl:35][C:36]1[N:41]=[C:40]([NH:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[C:39]([F:43])=[CH:38][N:37]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCc1cccnc1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Fc1cnc(Cl)nc1NCc1cccnc1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-pyridylmethylamine (162 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) reacted to give 5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 43%). 1H NMR (CD3OD): δ 4.71 (s, 2H), 6.38 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 6.88 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J=8.1 Hz, 1H), 7.14 (t, J=2.4 Hz, 1H), 7.37 (dd, J=4.8 and 7.8 Hz, 1H), 7.73 (d, J=3.6 Hz, 1H), 7.87 (dt, J=2.1 and 7.5 Hz, 1H), 8.39 (dd, J=1.2 and 7.8 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −170.99; LCMS: ret. time: 8.82 min.; purity: 92.90%; MS (m/e): 312.05 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH2:49]([CH2:51][NH2:52])[OH:50]>ClCCl>[OH:50][CH2:49][CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NCCO)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
See FIG. 20(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.24 mmol) was taken in dichloromethane (10 mL) to get a suspension. Added triethyl amine (0.0669 mL, 0.48 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.286 mL, 0.48 mmol). The reaction mass was stirred at RT for 5 minutes. Ethanol amine (0.029 mL, 0.48 mmol) was added and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with DCM, washed with water and brine solution. The DCM layer was dried over sodium sulphate, evaporated to get the crude compound which was purified by column chromatography. Yield-52.7%. ES+MS m/z: 356.4 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H ) 2.39 (s, 3 H) 3.39-3.65 (m, 4 H ) 3.93 (s, 3 H ) 4.84 (t, J=5.09 Hz, 1 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H) 8.33 (s, 1 H ) 8.41 (s, 1 H ) 8.80 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:29]([CH3:30])=[C:28]([C:31]#[N:32])[C:19]3[N:20]=[C:21]([C:23]([O:25]CC)=O)[O:22][C:18]=3[C:17]=2[F:33])[CH:13]=[CH:14][CH:15]=1.Cl>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:29]([CH3:30])=[C:28]([C:31]#[N:32])[C:19]3[N:20]=[C:21]([C:23]([N:3]([CH3:4])[CH3:2])=[O:25])[O:22][C:18]=3[C:17]=2[F:33])[CH:13]=[CH:14][CH:15]=1
Reactant: CNC
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3cccc(Cl)c3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2cccc(Cl)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
Dimethylamine hydrochloride (1.406 g, 17.27 mmol) was suspended in dichloromethane (20 ml), and under nitrogen atmosphere at 0° C., trimethylaluminium (1.03 M n-hexane solution) (16.8 ml, 17.27 mmol) was gradually dropwise added. After stirring at room temperature for 30 minutes, a dichloromethane (20 ml) solution of ethyl 6-(3-chlorophenyl)-4-cyano-7-fluoro-5-methyl-1,3-benzoxazole-2-carboxylate (I-310) (2.065 g, 5.75 mmol) was dropwise added at 0° C. The solution was stirred for 21 hours with gradually heating up to room temperature, then at 0° C., aqueous 1 N hydrochloric acid solution (50 ml) was dropwise added, taking 15 minutes. After stirring at the same temperature for 30 minutes, the reaction liquid was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:acetone=99:1, v/v) to obtain the entitled compound (1.641 g, 80%) as a pale yellow solid.
Reaction SMILES: B(F)(F)F.CCOCC.[N:10]([CH2:13][C@H:14]1[O:23][CH:18]([O:19][C:20](=O)[CH3:21])[C@H:17]([O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:28][C:29](=[O:31])[CH3:30])[C@H:15]1[O:32][C:33](=[O:35])[CH3:34])=[N+:11]=[N-:12].[CH:36]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=C(O)C=1.CCOCC>C(Cl)Cl>[C:25]([O:24][C@@H:17]1[C@@H:16]([O:28][C:29](=[O:31])[CH3:30])[C@@H:15]([O:32][C:33](=[O:35])[CH3:34])[C@@H:14]([CH2:13][N:10]=[N+:11]=[N-:12])[O:23][C@@H:18]1[O:19][C:20]1[CH:39]=[CH:40][C:41]([N+:42]([O-:44])=[O:43])=[CH:36][CH:21]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC1O[C@H](CN=[N+]=[N-])[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN=[N+]=[N-])O[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 15.4 %

Procedure:
Boron trifluoride diethyl etherate (80 μl, 0.70 mmol) was added to a stirred solution of 6-azido-6-deoxy-1,2,3,4-tetra-O-acetyl-D-galactopyranose 36 (α:β, 1:1) (52 mg, 0.139 mmol) in DCM (5 mL). The solution was stirred under argon at RT. After 20 min a solution of p-nitrophenol (19 mg, 0.14 mmol) in DCM (5 mL) was added to the reaction mixture and stirring under argon maintained. After 65 min, t.1.c. (DCM:ether, 60:1) indicated formation of two products (Rf 0.1, 0.4) with some remaining starting material (Rf 0.3). The DCM was removed in vacuo. The residue was diluted with chloroform (30 mL), washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (DCM:ether, 60:1) to afford p-nitrophenyl 2,3,4-tri-β-acetyl-6-azido-6-deoxy-α-D-galactopyranoside 40 (9.7 mg, 14%) as a colourless oil; partial data [α]D25 +18.3 (c, 0.5 in CHCl3); νmax (thin film) 3430 (br, OH), 2101 (sh, N3), 1637 (st, C═O)cm−1; δH (500 Mz, CDCl3) 2.05, 2.09, 2.21 (9H, 3 x s, 3 x CH3), 3.13 (1H, dd, J5,6 4.2 Hz, J6,6′ 13.1 Hz, H-6), 3.46 (1H, dd, J5,6′ 8.2 Hz, H-6′), 4.18 (1H, dd, H-5), 5.34 (1H, dd, J2,3 3.7 Hz, J2,3 10.9 Hz, H-2), 5.49 (1H, d, J3,4 3.0 Hz, H-4), 5.57 (1H, dd, H-3), 5.94 (1H, d, H-1) 7.21 (2H, J=9.3 Hz, 2 x CHCHCNO2), 8.26 (2H, 2 x CHCNO2); 5c (125.7 MHz, CDCl3) 19.9, 20.0, 21.0 (3 x q, 3 x CH3), 51.9 (t, C-6), 53.3 (d, C-2), 66.6 (d, C-3), 67.6 (d, C-4), 69.0 (d, C-5), 95.2 (d, C-1), 115.6, 115.7, 125.3 (3 x s, 3 x C═O), 116.9, 117.0 (2 x d, CHCHCNO2), 126.5, 126.6 (2 x d, CHCNO2), 140.8 (s, CNO2), 167.2, 169.9, 170.2, 171.8 (4 x s, 3 x C═O, 1x CCHCHCNO2); m/z (CI+) 470 (M+NH4+, 10%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:12].Cl[C:14]1[N:19]=[C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=1>>[Cl:32][C:17]1[C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:19][C:14]([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[S:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[CH:1]=2)=[N:15][CH:16]=1
Reactant: CS(=O)(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CNCCS2
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CNCCS3)ncc1Cl
Yield: 84.9 %

Procedure:
Following the procedure of 2f, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00039 mol) and N-[(1S,2R)-2-(2,5-dichoro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.13 g, 0.00039 mol) were reacted giving N-{(1R,2R)-2-[5-chloro-2-(6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (0.16 g, 85%). MP: 141-3° C.; 1H-NMR (DMSO-d6) 9.30 (s, 1H), 7.93-5 (s, 1H), 7.73-9 (s, 1H), 7.44-6 (d, 1H), 7.33-5 (d, 1H), 7.16-8 (d, 1H), 6.76-8 (d, 1H), 3.91 (s, 1H), 3.84-5 (m, 1H), 3.22-4 (m, 2H), 2.93 (s, 2H), 2.63-4 (m, 2H), 2.00-12 (m, 2H), 1.70 (m, 2H), 1.27-37 (m, 4H); LC/MS (ESI+): 483 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)[CH3:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH2:18][CH3:19])=[CH:25][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(CC)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.4 g, 6.8 mmol) and allowed to stir for 10 min at RT. 2-Ethyl-5-vinyl-pyridine (0.28 g, 2.04 mmol) was added and stirred for further at 100 deg C. for 18 h. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.025 g, 10% yield). 8-Chloro-5-[2-(6-ethyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.07 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.009 g, 0.07 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.010 g, 32% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=[O:36])=[CH:29][CH:28]=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[OH:36])=[CH:31][CH:32]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(CC=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A stirring solution of 10.8 mL (0.077 mole) of diisopropylamine in 100 mL of tetrahydrofuran is cooled to 0° C., and 30.8 mL (0.077 mole) of n-butyllithium (2.5M in hexanes) is added dropwise. Upon completion of the addition, the reaction mixture is stirred for about 10 minutes, then 22.3 grams (0.077 mole) of tributyltin hydride is added dropwise at a rate to maintain the reaction mixture temperature at about 0° C. The reaction mixture is then stirred for about 15 minutes. After this time the reaction mixture is cooled to -78° C., and a solution of 13.8 grams (0.077 mole) of 3-(4-fluorophenyl)-3-methylbutyraldehyde in about 15 mL of tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition, the reaction mixture is stirred at -78° C. for ten minutes. After this time the reaction mixture is quenched by the dropwise addition of 300 mL of aqueous 10% ammonium chloride. The mixture is then extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, at a temperature of less than 30° C., yielding 36.3 grams of 3-(4-fluorophenyl)-3-methyl-1-tributylstannylbutanol. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:10]([CH3:16])=[C:11]([C:12](=[O:15])[CH2:13][Cl:14])[C:3]=12.[NH2:26][CH:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:30][CH2:29][CH2:28][CH:27]([NH:26][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:10]([CH3:16])=[C:11]([C:12](=[O:15])[CH2:13][Cl:14])[C:3]=12)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC(N)CCC
Reactant: Cc1cc(C)c(-n2c(C)c(C(=O)CCl)c3c2=NC(C)NC=3Cl)c(C)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(CCC)NC1=c2c(C(=O)CCl)c(C)n(-c3c(C)cc(C)cc3C)c2=NC(C)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of compound (7) (730 mg, 2 mmol), 4-aminoheptane (250 mg, 2.2 mmol) and triethylamine (250 mg, 2.5 mmol) were stirred at ambient temperature for 16 hours. The solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to provide compound (8).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]2[CH2:16][CH2:15][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]=1)[C:8]2=3)=[O:5])C.O.Cl>C(O)C.[OH-].[Na+]>[CH:14]1[C:13]2[C:8]3=[C:9]([CH2:15][CH2:16][N:7]3[C:6]=1[C:4]([OH:5])=[O:3])[CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)c1cc2cccc3c2n1CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cccc3c2n1CC3
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid ethyl ester (1.117 g) in ethanol (25 ml) and 2M sodium hydroxide (25 ml) was heated to reflux for 1 hour. The mixture was cooled to room temperature and poured into water (300 ml). 1M hydrochloric acid was added until pH1 and the precipitate formed filtered off and washed with water (50 ml). After drying under reduced pressure 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid was obtained as a pale yellow powder (884 mg). 400 MHz 1H NMR (DMSO-d6) δ: 12.94 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.01-6.96 (m, 3H), 4.67 (t, J=6.8 Hz, 2H), 3.74 (t, J=6.8 Hz, 2H); LCMS: 188 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]2[N:32]=[C:33]([NH2:35])[S:34][C:30]=2[CH:29]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:35][C:33]3[S:34][C:30]4[CH:29]=[C:28]([F:27])[CH:37]=[CH:36][C:31]=4[N:32]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1nc2ccc(F)cc2s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1nc2ccc(F)cc2s1
Yield: 37.4 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 6-fluorobenzo[d]thiazol-2-amine (0.067 g, 0.397 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of desired product. 1H NMR (DMSO-d6): δ 3.99 (s, 3H), 7.32 (t, J=7.2 Hz, 1H), 7.51 (t, J=9.3 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.68-7.80 (m, 4H), 7.94 (t, J=6.3 Hz, 2H), 11.98 (s, 1H), 12.83 (br s, 1H); MS (m/z): 512.97 [M−H]−.