Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[OH:23])=[CH:24][CH:25]=1
Reactant: O=C(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
Stir 0.8 g of 2-(4-chlorobenzyl)-1-[3-(4-fluorobenzoyl)propyl]pyrrolidine at room temperature for 3 hours with 0.5 g of sodium borohydride in 8 ml of methanol/2 ml of water. Concentrate the resulting reaction mixture and then take up the concentrate with water/diethyl ether. Dry the ethereal phase over sodium sulfate and distil off the solvent to obtain the title compound as light-brown viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]([CH3:19])=O)[CH3:13].[NH2:21][C:22]([NH2:24])=[S:23].Cl>C(O)C>[CH3:19][C:17]1[NH:24][C:22](=[S:23])[NH:21][CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]=1[C:15]([O:14][CH2:12][CH3:13])=[O:20]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(=S)NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution containing m-nitrobenzaldehyde (7.55 g., 50.0 mmole), ethylacetoacetate (6.5 g., 50.0 mmole), and thiourea (3.8 g., 50.0 mmole) in absolute ethanol (30 ml.) is treated with concentrated hydrochloric acid (0.2 ml.). The resulting reaction mixture is heated at reflux for 6 hours. It is then cooled to room temperature and triturated. A small amount of a white solid precipitates out. The reaction flask is then allowed to cool in the refrigerator overnight. The precipitate that forms is filtered off and washed with additional absolute ethanol to provide 2.5 g. of colorless solid product. Recrystallization from absolute ethanol gives an analytically pure sample of 1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, ethyl ester; m.p. 208°-209°. TLC (silica gel; ethyl acetate:hexane, 1:1) Rf =0.45.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:18][CH2:19][C@H:20]2[CH2:22][O:21]2)[S:9]1(=[O:24])=[O:23].C(O)C.[CH3:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:18][CH2:19][C@H:20]([OH:21])[CH2:22][NH:29][CH3:28])[S:9]1(=[O:23])=[O:24]
Reactant: O=S1(=O)N(CC[C@H]2CO2)Cc2ccccc2N1c1ccccc1F
Reactant: CN
Solvent: CCO
Product: CNC[C@@H](O)CCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 100 °C
Yield: 80 %

Procedure:
1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.12 g, 0.29 mmol) was dissolved in an 8 M solution of methylamine in ethanol (3 mL, 24 mmol) and was heated to 100° C. for 192 sec. in the microwave. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO2, 0-5% 7 M NH3-methanol/dichloromethane). The purified free-base was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to provide (2S)-4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-1-(methylamino)butan-2-ol (0.10 g, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][C:34]([CH3:36])=O.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:29])[C:21]4([C:25]([NH:27][CH3:28])=[O:26])[CH2:24][N:23]([CH:34]([CH3:36])[CH3:33])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CN(C(C)C)C1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
The hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylazetidine-3-carboxamide (110 mg, 0.22 mmol Example 99), acetone (23 μl, 0.31 mmol) and diisopropylethylamine (78 μl, 0.45 mmol) were stirred at room temperature in 5% acetic acid in 1,2-dichloroethane (2 ml) with 3 Å molecular sieves, and sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added portionwise over 0.5 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting product was purified on preparative HPLC (standard basic conditions) to give the title product (52 mg, 47%) as a white powder; 1H NMR Spectrum: (CDCl3) 0.98 (d, 6H), 2.41 (s, 3H), 2.49 (m, 1H), 2.90 (s, 3H), 3.25 (brs, 2H), 3.57 (m, 2H), 3.96 (s, 2H), 3.97 (s, 3H), 7.16 (m, 2H), 7.24 (s, 1H), 7.57 (brs, 1H), 7.78 (brs, 1H), 8.00 (brs, 1H), 8.54 (brs, 1H), 8.73 (s, 1H); Mass Spectrum: (M+H)+ 501.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]([C:11]([OH:13])=O)=[N:8][NH:9][CH:10]=1.[NH2:19][C:20]1[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23].C(Cl)CCl.C1C=CC2N([OH:42])N=NC=2C=1>CN(C=O)C>[NH2:19][C:20]1[C:21]([CH2:22][OH:23])=[CH:24][CH:25]=[CH:26][C:27]=1[NH:28][C:11]([C:7]1[C:6]([NH:5][C:4](=[O:42])[C:3]2[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:2]=2[F:1])=[CH:10][NH:9][N:8]=1)=[O:13]
Reactant: Nc1cccc(CO)c1N
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1n[nH]cc1NCc1c(F)cccc1F
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Nc1c(CO)cccc1NC(=O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture of 4-(2,6-difluorobenzylamino)-1H-pyrazole-3-carboxylic acid (1.0 g, 3.7 mmol) (Example 16D), 2,3-diaminobenzylalcohol (560 mg, 4.1 mmol), EDC (870 mg, 4.5 mmol) and HOBt (610 mg, 4.5 mmol) in DMF (20 ml) was stirred at ambient temperature for 18 h and then reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:1, 2:1)] to give 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (2-amino-3-hydroxymethyl-phenyl)-amide (860 mg).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[Cl:17][C:18]1[N:23]=[N:22][C:21]([NH2:24])=[CH:20][CH:19]=1.O>C(O)CCC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:24]=2)[N:23]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: O
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4ccc(Cl)nn34)cc2s1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (1.5 g, 5.5 mmol) and 6-chloropyridazin-3-amine (1.4 g, 11 mmol) in 1-butanol (60 mL) was heated at reflux overnight. Then the mixture was cooled to rt and water (120 mL) was added. The mixture was extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a yellow solid (1.6 g, 84%). 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=9.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (dd, J=0.6, 1.2 Hz, 1H), 7.53 (s, 1H), 7.37 (dd, J=1.8, 8.4 Hz, 1H), 7.03 (d, J=9.3 Hz, 1H), 4.40 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25](Br)([CH3:27])[CH3:26].O>CN(C)C=O>[CH:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH3:27])[CH3:26]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1

Procedure:
12 g of 7-hydroxy-isoflavone are boiled for 2 hours under a reflux condenser with 10 g of potassium carbonate and 9 g of isopropyl bromide in 40 ml of dimethyl formamide. On pouring the reaction mixture into water, the separated product is recrystallized from acetone, yielding 7-isopropoxy-isoflavone. In a similar way all the other isoflavone derivatives described in Example 7 can be prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH2:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:22][S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: COc1cccc(S)c1
Reactant: C=C(C(=O)O)c1ccc(OC)cc1
Product: COc1ccc(C(CSc2cccc(OC)c2)C(=O)O)cc1
Temperature: 125 °C
Reaction time: 21 h

Procedure:
3-Methoxybenzenethiol(2.5 ml, 20.1 mmol) was added to 2-(4-methoxyphenyl)acrylic acid (3 g, 16.8 mmol) and stirred for 21 hours with heating at 125° C. The reaction solution was extracted with diethyl ether, and the ether solution was washed with 0.1N iodine-potassium iodide solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to remove the organic solvent to obtain the title compound as a brown oil. The resulting compound was used in the next reaction without further purification.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9](#[N:11])[CH3:10].[CH:12]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH:24]=[O:25])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.C1COCC1>[CH:12]1([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:24]([OH:25])[CH2:10][C:9]#[N:11])[CH:26]=[CH:27][CH:28]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=Cc1cccc(OCC2CCCCCC2)c1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: N#CCC(O)c1cccc(OCC2CCCCCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of LDA (10 mL of a 2M solution in heptane/THF/ethylbenzene, 20.09 mmol) in THF (30 mL) was added acetonitrile (0.97 mL, 18.41 mmol) dropwise over ca. 2 min. After stirring for 15 min, a solution of 3-(cycloheptylmethoxy)benzaldehyde (3.89 g, 16.74 mmol) in THF (20 mL) was added. The reaction was allowed to warm to 0° C. over 2 h then quenched with the addition of saturated aqueous NH4Cl (30 mL). The mixture was extracted with EtOAc twice. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (20% EtOAc-hexanes) gave 3-(3-(cycloheptylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (2.102 g, 46%): 1H NMR (400 MHz, DMSO-d6) δ 7.22 (t, J=8.0 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.81 (ddd, J=8.4, 2.4, 0.8 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 4.83 (dt, J=6.4, 4.8 Hz, 1H), 3.71 (d, J=6.8 Hz, 2H), 2.86 (dd, J=16.8, 5.0 Hz, 1H), 2.78 (dd, J=16.4, 6.6 Hz, 1H), 1.86-1.92 (m, 1H), 1.76-1.82 (m, 2H), 1.61-1.67 (m, 2H), 1.37-1.59 (m, 6H), 1.20-1.30 (m, 2H).*
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH:27]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([CH3:29])[CH3:28]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:42]2[CH2:43][CH2:44][N:39]([C:31]3[N:30]([CH:27]([CH3:29])[CH3:28])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=3)[CH2:40][CH2:41]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CC(C)n1c(N2CCNCC2)nc2ccccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CC(C)n1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-isopropyl-2-(piperazin-1-yl)-1H-benzimidazole.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C@H:9]2[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@@H:24]([NH2:28])[C@@H:23]([O:29][CH3:30])[CH2:22]2.C(N(CC)C(C)C)(C)C.C(Cl)Cl>CN1CCCC1=O>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@@H:24]([NH:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C@H:9]3[CH2:13][C@H:12]([OH:14])[C@H:11]([CH2:15][OH:16])[CH2:10]3)[CH:3]=1)[C@@H:23]([O:29][CH3:30])[CH2:22]2
Reactant: OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O)C2)ncn1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
To a 500 ml Parr pressure vessel was added (1S,2S,4R)-4-(6-chloropyrimidin-4-yloxy)-2-(hydroxymethyl)cyclopentanol (26) (25.00 g, 102.2 mmol) in N-methylpyrrolidinone (200 mL). To this mixture was added (1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (31.10 g, 132.8 mmol) followed by N,N-diisopropylethylamine (88.99 mL, 510.9 mmol). The vessel was then sealed, pressurised with 30 psi of nitrogen and heated to 130° C. for 22 hours. The pressure increased to 50 psi when the reaction reached temperature and held during the course of the reaction. After 22 hours the reaction was cooled to ambient temperature and the pressure was vented. Methylene chloride (250 mL) was added to the reaction mixture and this was then extracted with saturated sodium bicarbonate in water (250 mL). The organic layer was then extracted four times with water (250 mL) and once with saturated sodium chloride in water (250 mL). The organic layer was then dried over sodium sulfate (7.5 g), filtered and concentrated. To the black semisolid oil was added acetonitrile (250 mL) and the mixture was stirred for 2 hours at ambient temperature. During this time a beige solid precipitated and was filtered and dried under reduced pressure at 40° C. for 16 hours. A light biege solid was afforded (17 g, 41%). 1H NMR (300 MHz, CD3OD, δ): 8.19 (s, 1H), 7.25 (s, 1H), 7.18 (m, 2H), 5.97 (s, 1H), 5.58 (m, 1H), 5.30 (m, 1H), 4.41 (m, 1H), 4.22 (m, 1H), 3.76 (m, 1H), 3.61 (m, 1H), 3.30 (s, 3H), 3.05 (m, 2H), 2.30 (m, 2H) and 1.97 (m, 3H).
Reaction SMILES: [O:1]1[CH2:21][C@@H:2]1[CH2:3][O:4][C:5]1[C:6](C=O)=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2.ClC1C=C(C=CC=1)[C:26]([O:28]O)=[O:27].FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:21][C@@H:2]1[CH2:3][O:4][C:5]1[C:6]([O:28][CH:26]=[O:27])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cc2c(C=O)c(OC[C@H]3CO3)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(OC=O)c(OC[C@H]3CO3)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of ethyl (R)-5-(2,3-epoxypropoxy)-4-formylindole-2-carboxylate (1.95 g; prepared by the method described above) in dichloromethane (40 ml) was cooled to 0° C. 3-Chloroperoxybenzoic acid (85%; 1.75 g) was then added in one portion followed by a solution of trifluoroacetic acid (0.77 g) in dichloromethane (10 ml), in portions. The mixture was stirred at 0° C. for 10 minutes and then at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane (300 ml), washed successively with saturated aqueous sodium bisulphite solution (100 ml), saturated aqueous sodium bicarbonate solution (3×150 ml), dried over sodium sulphate and the solvent evaporated. The solid residue was purified by flash chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate to give ethyl (R)-5-(2,3-epoxypropoxy)-4-formyloxyindole-2-carboxylate (1.55 g) as a pale yellow crystalline solid; m.p. 123-125° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22].C(N(CC)CC)C.[CH:30]([C:32]([CH3:34])=[O:33])=[CH2:31]>CC(C)=O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][CH2:30][C:32](=[O:33])[CH3:34])[CH2:20][CH2:21]2)=[O:13])=[CH:4][C:3]=1[Cl:22]
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Reactant: C=CC(C)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Yield: 37.1 %

Procedure:
4-Piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate (0.100 g; 10.31 mmol) was dissolved in acetone (10 ml) and treated with triethylamine (0.043 ml; 0.31 mmol) and methyl vinyl ketone (0.026 ml; 0.34 mmol). The solution was heated at reflux (18 hours), cooled and evaporated in vacua to a yellow gum. The gum was purified by flash silica-gel chromatography with CHCl3 as eluant to yield the title compound as a colourless gum (0.050 g; 41%) which was converted to the oxalate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:51][O:52][CH2:53][CH2:54][CH2:55][NH2:56]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:56][CH2:55][CH2:54][CH2:53][O:52][CH3:51])=[O:28])=[CH:29][CH:30]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Reactant: COCCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCCNC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.7 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 3-methoxy-propylamine (10 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 100% ethyl acetate) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-methoxy-propyl)-benzamide (21 mg, 46%) as a white powder: ESI-LRMS m/e calcd for C30H37ClN4O5S [M+] 600.22, found 601.47 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.23 (m, 2H, CH2), 1.45-1.98 (m, 10H, 5×CH2), 2.12-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.39 (s, 3H, OCH3), 3.51-3.70 (m, 5H, 2×CH2 and CH), 5.20 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 6.97 (brm, 1H, NH), 7.18 (d, Jo=8.1 Hz, 2H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.71 (d, Jo=8.1 Hz, 2H, Ar), 8.07 (d, Jo=8.1 Hz, 1H, Ar), 8.16 (s, 1H, NH).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:23][CH2:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH3:26])=[C:15]([N+:20]([O-])=O)[CH:16]=[N:17]2)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pt].C(#N)C>[NH2:20][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[NH:23][CH2:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:26])[CH3:27])=[CH:12][CH:11]=[C:10]([O:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:19]=2
Reactant: [H][H]
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(OC(=O)c3ccccc3)ccc12)NC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NC(=O)OC(C)(C)C
Yield: 98.6 %

Procedure:
tert-Butyl [2-(7-benzoyloxy-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (6.74 g), 5% platinum on carbon (1.02 g), and acetonitrile (125 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent and the filtrate was concentrated under reduced pressure to give 6.04 g of tert-butyl [2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as an orange foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].[C:22](=O)([O-])[O-].[K+].[K+].Cl.S(=O)(=O)(O)O>CO.O>[N+:12]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:22])=[O:10])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccccc1Oc1cccc([N+](=O)[O-])c1
Temperature: 130 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
A mixture of 2-bromophenylacetic acid (21.5 g), 3-nitrophenol (29.2 g), potassium carbonate (27.6 g) and cuprous chloride (0.5 g) was heated with stirring at 130° C. for 6 hours. After cooling, the mixture was poured into water (500 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×200 ml). The extracts were dried, filtered and concentrated to give a dark oil. The oil was dissolved in methanol (400 ml) containing concentrated sulphuric acid (4 ml) and the resulting solution was heated at reflux for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (300 ml). This solution was washed successively with sodium hydroxide (2×100 ml of 1M aqueous solution) and brine, then dried, filtered and concentrated to give a dark oil. Bulb-to-bulb distillation of this oil (220° C. oven temperature, 0.2 mmHg) gave methyl 2-(3-nitrophenoxy)phenylacetate (16.74 g, 58% yield from 2-bromophenylacetic acid) as a clear pale oil.