Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15]N)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C([N:19](CC)CC)C.[C:24](Cl)(=[O:30])/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH3:29]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][C:25](=[CH:26][CH2:27][CH2:28][CH3:29])[C:24]([NH2:19])=[O:30])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCC/C=C/C(=O)Cl
Reactant: CCN(CC)CC
Reactant: COc1cc(NCCN)c2ccccc2n1
Solvent: ClCCl
Product: CCCC=C(CCNc1cc(OC)nc2ccccc12)C(N)=O
Reaction time: 0.17 h

Procedure:
N-(2-Methoxy-4-quinolyl)ethane-1,2-diamine (21.7 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (1 ml) together with triethylamine (17.4 μl, 0.125 mmol). (E)-hex-2-enoyl chloride (16.6 mg, 0.125 mmol) was added and the mixture was shaken for 10 minutes, diluted with dichloromethane and washed with 10% sodium bicarbonate solution (2 times), water and evaporated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 3.4 mg (0.0109 mmol, 11%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1>>[CH:29]([OH:31])=[O:30].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][F:20])=[CH:28][N:27]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: O=C(O)c1ccc(OCF)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCF)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-fluoromethoxy-pyridine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as an off-white amorphous material. MS (ISP): m/z=427.2 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1F.[Li]CCCC.C1CCCCC1.[N:20]1[C:27](Cl)=[N:26][C:24]([Cl:25])=[N:23][C:21]=1[Cl:22].C1C[O:32][CH2:31]C1>ClCCl.C(Cl)(Cl)Cl>[Cl:22][C:21]1[N:23]=[C:24]([Cl:25])[N:26]=[C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:32][CH3:31])[CH:3]=2)[N:20]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1CCOC1
Reactant: Fc1ccccc1I
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COc1cccc(-c2nc(Cl)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-iodo-2-fluorobenzene (2.22 g, 10 mmol) in THF (15 mL) was cooled in a dry-ice/acetone bath and then treated dropwise with a solution of nBuLi in cyclohexane (5 mL, 2M, 10 mmol) under nitrogen. The mixture was stirred cold for 30 minutes and then transferred by cannula into a solution of cyanuric chloride (1.84 g, 10 mmol) in THF (20 mL) along with a rinse with THF (5 mL). The mixture was stirred cold for 10 minutes and then allowed to warm to room temperature for 2 hours. The reaction was poured into a mixture of saturated sodium bicarbonate (25 mL) and water (25 mL) and stirred for 15 minutes. Treated with hexanes (50 mL), shaken in a separatory funnel and separated layers. The organic layer was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield yellow oil. The oil was diluted with a small amount of dichloromethane and loaded onto 100 g of silica gel. The silica gel was eluted with 10% ethyl acetate/hexanes. The appropriate fractions were concentrated on a rotary evaporator to yield slightly yellow oil. The oil was diluted with chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with ethyl acetate/hexanes (2.5%, 5%, 7.5%). The appropriate fractions were concentrated on a rotary evaporator to yield 2,4-dichloro-6-(2-fluorophenyl)-1,3,5-triazine (VIII) as a white solid (0.842 g). ESI/MS 244.0, 246.0, 248.0 (M+H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](I)[CH:14]=[CH2:15]>CS(C)=O.O>[CH2:15]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH:14]=[CH2:13]
Reactant: C=CCI
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCn1ccc2cc(Br)ccc21
Yield: 60.6 %

Procedure:
To a stirred mixture of NaOH (204 mg., 5.1 mmol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for three hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added allyl iodide (0.466 mL., 5.1 mmol., 1 eq.) via syringe. After 2 h. the mixture was diluted with water and extracted 2×with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product was purified by flash column chromatography on silica gel (4:1 hexanes/acetone) affording 730 mg 1-allyl-5-bromoindole.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[K+]>C(O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccccc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)cc2)Cc2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 100 g of indanone, 112 g of p-chlorobenzaldehyde and 500 ml of ethanol is stirred, the resulting solution is cooled to -10° and treated rapidly (3 minutes) with a solution of 5.0 g of KOH in 100 ml of ethanol. The solution is allowed to warm and the product begins to crystallize at 17° (cooled to keep under 15°). The resulting slurry is allowed to stir at 20°-25° for 1 hour, and then poured onto 2 liters of icewater. After standing for 3 hours, the solid is filtered, washed with cold water and allowed to air dry; wt., 190 g, m.p. 174°-179°. After crystallization from 400 ml of DMF, the cream-colored solid weighs 164.5 g (86%), m.p. 177°-179°.
Reaction SMILES: CN[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([Li])[CH2:13][CH2:14]C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:19].Cl>O1CCCC1.C(OCC)(=O)C.CC(C)=O>[CH3:12][C:13]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:3](=[O:19])[O:4]1
Reactant: CNC(=O)c1ccc(C)cc1
Reactant: [Li]CCCC
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)C(C)(C)OC2=O

Procedure:
A suspension of N-methyl-4-toluamide (100 g) in anhydrous tetrahydrofuran (2 l) was cooled to -28° and n-butyl lithium (580 ml of 2.5M solution in hexanes) was added dropwise maintaining the temperature at -20° to -25°. The resultant solution was stirred at -20° for 2 h, then cooled to -42° and acetone (175 ml) added dropwise maintaining the temperature below -42°. Stirring was continued at -35° to -42° for 1 h before glacial acetic add (39 ml) was added. The mixture was stirred without further cooling for 90 min and then poured into aqueous HCl (1N, 1.4 l) and ethyl acetate (0.5 l). The organic phase was washed with brine (3'1 l), dried over sodium sulphate and concentrated and dried in vacuo. The solid was dissolved in hot methylene chloride (350 ml) and cooled to 3°. The filtrate was treated with hexane (50 ml) and cooled to 3°. The filtrate was dissolved in methylene chloride (1 l) and heated to reflux in the presence of aqueous HCl(6N, 1 l) for 6 h. The organic phase was separated and again heated to reflux in the presence of aqueous HCl (6N, 1 l) for 7 h. The organic phase was separated and washed with saturated aqueous sodium bicarbonate (2'1 l) and concentrated in vacuo to give 3,3,5-trimethyl-3H-isobenzofuran-1-one. HPLC and NMR data were consistent with the product obtained in Preparation A (a) and with its structure.
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>N1C=CC=CC=1>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[S:24]([CH3:27])(=[O:26])=[O:25])[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1C2CN3OC(O)(C(COC(N)=O)c4c(O)cc(C=O)cc43)C21
Reaction time: 1 h

Procedure:
4-Formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) was dissolved in pyridine (1.19 ml) containing mesyl chloride (12 μl). The solution was stirred for 1 hour in a dry ice-carbon tetrachloride bath under nitrogen atmosphere. The solution was evaporated in vacuo and the residue was subjected to preparative thin layer chromatography. Development was carried out with a mixture of chloroform and methanol to afford 4-formyl-6,9-dihydroxy-11-mesyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (47 mg).
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][NH:28][CH3:29])=[CH:19]1.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:28]([CH3:29])[CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]([CH3:17])[CH:19]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cn(C)c2ccccc12
Reactant: Nc1ccc(C=CC(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
EDC (0.35 g, 1.89 mmole) was added to a solution of 3-(6-aminopyridin-3-yl)acrylic acid (0.31 g, 1.89 mmole). 1-methyl-3-(methylaminomethyl)-1H-indole (0.30 g, 1.72 mmole), HOBt.H2O (0.24 g, 1.89 mmole) and diisopropylethylamino (0.60 mL, 3.44 mmole) in DMF (20 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (5% MeOH/CHCl3) gave the title compound (0.30 g, 55%) as a light yellow solid: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.O>N1CCCCC1.CC(O)C>[F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:9]\[C:8]1[NH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1Cc2c(ccc(F)c2I)N1
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: O
Product: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Temperature: 85 °C

Procedure:
A mixture of 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (1.40 g, 5.05 mmol) (see Starting Material 10), and excess 2-pyrrolecarboxyaldehyde (0.60 g, 6.3 mmol) (Aldrich) in 1% piperidine in 2-propanol (20 mL) was heated at 85° C. for 2.25 h. Hot water (20 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 1.50 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12]SC)[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1.O[O:24][S:25]([O-:27])=O.[K+].[CH3:29]O>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][S:25]([CH3:29])(=[O:27])=[O:24])[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1
Reactant: CSCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a degassed solution of 2-chloro-11-fluoro-6-((methylthio)methyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (100 mg, 0.3 mmol) in MeOH (2 mL) was added a solution of Oxone (185 mg, 0.3 mmol) in H2O (2 mL) at 0° C., and the mixture was stirred at 25° C. for 24 h. Then the mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (DCM:EA=10:1) to afford the desired product of 2-chloro-11-fluoro-6-((methylsulfonyl)methyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (70 mg, yield: 64%). 1H-NMR (CDCl3, 400 MHz) δ 7.62 (d, J=7.6 Hz, 1H), 7.43 (s, 1H), 7.22˜7.29 (m, 3H), 6.83˜6.89 (m, 1H), 5.45˜5.51 (m, 1H), 3.51˜3.62 (m, 2H), 3.14˜3.21 (m, 1H), 2.97˜3.05 (m, 1H), 2.84 (s, 3H). MS (M+H)+: 365/367.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C.[Pt]>[CH2:28]([O:27][C:25](=[O:26])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 34.9 g of 1-benzyloxy-2-fluoro-4-nitrobenzene (WO 03 064413) (MW: 247.28, 141 mmol) and 340 mg of platinum (5% on activated carbon) in 350 ml of ethyl acetate was stirred at RT and normal pressure under a hydrogen atmosphere. The course of the reaction was monitored by HPLC and the reaction was terminated after 20 h. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure using a rotary evaporator. The oily residue was dissolved in 500 ml of acetone and 250 ml of a saturated sodium hydrogen carbonate solution and 17.5 g of sodium hydrogen carbonate (MW: 84.01, 208 mmol) were added. The mixture was cooled to 5° C. and 26.08 g of benzyl chloroformate (MW: 170.59, 152 mmol) were added dropwise. The mixture was then stirred for 2 h at RT and the course of the reaction was monitored by TLC (hexane/ethyl acetate 3:1). The acetone was removed under reduced pressure, 500 ml of water were added to the residue, and the solid material was filtered off. The crystals were washed with 500 ml of water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4.C=O.[C:24]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:24])[C@@H:9]3[CH2:13][C:14]4[C:19]([C@H:8]3[C:7]=2[CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1Cl)CCN[C@@H]1Cc3ccccc3[C@@H]21
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc2c(cc1Cl)CCN(C)[C@@H]1Cc3ccccc3[C@@H]21
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of 300 mg (1.00 mmol) of Compound P from step E was dissolved in 20 mL acetonitrile and 0.40 mL (5.3 mmol) 37% aqueous formaldehyde was added followed by 0.10 grams (1.59 mmol) sodium cyanoborohydride. After 30 minutes, the solution was brought to pH 7 by dropwise addition of glacial acetic acid then stirred an additional 1 hour and 45 minutes. The solvent was removed under reduced pressure, and the residue was taken up into 125 mL ethyl acetate. This was washed with 50 mL 10% sodium bicarbonate, dried (MgSO4) and evaporated to give an oil, which was purified by flash chromatography over silica gel, eluting with ethyl acetate to give 150 mg of trans-5,6,7,7a,8,12b-hexahydro-2-methoxy-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine (Compound Q) as an oil, 200 MHz NMR (CDCl3) d 2.17(dd,1H,J=12,Hz), 2.69(m,2H) 2.37(s,3H), 2.90-3.40(m,4H), 3.77(s,3H), 4.67(d,1H,J=9 Hz), 7.03(s,1H), 7.17(s,1H), 7.20-7.35(m,4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:16]3[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3cc[nH]c3c2)CC1

Procedure:
Prepared from 1H-indole-6-carboxylic acid (4.0 g, 24.84 mmol, 1.0 eq) and tert-butyl piperazine-1-carboxylate (4.6 g, 24.84 mmol, 1.0 eq) in an analogous manner as described under procedure 1a). White solid. Yield: 5.0 g (61% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10].[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[CH2:14]([O:21][C:22]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOCCOCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COCCOCCNC(=O)OCc1ccccc1
Reaction time: 2.5 h

Procedure:
A suspension of 6.7 g (12.5 mmol) of 2-[2-(aminoethoxy)ethoxy]-acetic acid in 30 ml of THF and 10 ml of water is adjusted to pH 10 with 2N NaOH, and reacted dropwise with 1.95 ml of chloroformic acid benzyl ester (Fluka, Buchs, Switzerland). While the mixture is being stirred for 2.5 h, the pH is maintained between 9 and 9.5 by 2N NaOH. After concentration of the reaction mixture under reduced pressure, the resulting aqueous phase is washed twice with ethyl acetate, adjusted to pH 1.8 with 2N sulfuric acid and extracted 3 times with ethyl acetate. The combined organic phases are then washed with water and brine, dried and concentrated under reduced pressure. The title compound so obtained is further used without being further purified. TLC Rf (ethyl acetate/acetic acid: 9/1)=0.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.[Li+].[Br-].P(Br)(Br)[Br:19].O>CN(C=O)C>[Br:19][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCc1ccccc1-c1ccc(Cl)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccccc2CBr)cc1
Reaction time: 1 h

Procedure:
To a mixture of Example 37A (7.9 g) and LiBr (3.45 g) in DMF (100 mL) at 0° C. was added PBr3 (3.77 mL) and the reaction was stirred for 1 hour. The reaction was poured into water (400 mL), and the mixture was extracted with ether (3×200 mL). The combined ether layers were washed with 3× water, and brine, dried over Na2SO4, and condensed to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:20][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCCC1NCCc1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with phenethylamine (2.41 mL, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product, 2-phenethylamino-cyclopentanecarboxylic acid ethyl ester (1.94 g, 7.42 mmol, 38.6%), as a light yellow solid. LC-MS (ESI) calcd for C16H23NO2 261.17, found 262.2 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH:29]=O)[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+].[Cl:42]C(Cl)C>CO.C(O)(=O)C>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH2:29][N:31]5[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]5)[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:42]
Reactant: O=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(Cl)Cl
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cl
Product: O=C(O)C1CN(Cc2ccc3c(c2)CCc2c-3n[nH]c2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 60 °C
Reaction time: 14 h
Yield: 21 %

Procedure:
To 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydro-2H-benzo[g] indazole-7-carbaldehyde (Preparation 22C, 0.15 g, 0.366 mmol) in methanol (2 mL) and dichloroethane (2 mL) was added azetidine-3-carboxylic acid (0.044 g, 0.440 mmol) at room temperature followed by 5 drops of acetic acid. The reaction mixture was heated at 60° C. for 1 h, cooled to room temperature, and sodium cyanoborohydride (0.028 g, 0.440 mmol) was added in one lot. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and the resulting brown oil was partitioned between dichloromethane (20 mL) and water (10 mL). The cloudy dichloromethane layer was separated, washed with brine (10 mL), dried over sodium sulfate, and concentrated. To the resulting semi-solid material was added methanol (5 mL) and the contents were triturated and filtered. The filtrate was concentrated under reduced pressure and purified using Prep. HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the product were collected and concentrated. LCMS indicated the fraction to be a mixture of the desired product and methyl ester. The pH of the residual solution was adjusted to ˜5 with 1N sodium hydroxide. The resulting solid out was filtered and washed with water (2×5 mL), ethyl acetate (2×5 mL) and dried. The solid was dissolved in acetonitrile (3 mL) and 6N hydrochloric acid (3 mL) and the contents were heated at 90° C. for 2.5 h. LCMS indicated the fraction to be a mixture of the desired product and the methyl ester. The contents were heated at 90° C. for an additional 4 h. The reaction mixture was concentrated and azeotroped twice with THF (5 mL). The pale yellow solid was triturated with acetonitrile (3 mL), filtered, washed with acetonitrile (2×3 mL) and dried to yield 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydro-2H-benzo[g]indazol-7-yl)methyl)azetidine-3-carboxylic acid, hydrochloric acid (0.04 g, 0.075 mmol, 21% yield). The compound had an HPLC retention time=2.88 min (condition A); LC/MS M+1=495.1.