Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[C:13]([S:17][Na])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([S:17][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)S[Na]
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Ethyl 4-fluorobenzoate (1.5 g, 8.9 mmol) and tert-butylsulfanylsodium (2.0 g, 17.8 mmol) were combined in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 80° C. for 2 hours. After this time, a precipitate formed and N,N-dimethylformamide (15 mL) was added and the reaction mixture was stirred for an additional 20 hours at 80° C. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was acidified with 4M hydrochloric acid, extracted with ethyl acetate (2×). The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to yield 4-(tert-butylthio)benzoic acid as a colorless oil. The oil was dissolved in acetic acid (10 mL) and hydrogen peroxide (5 mL of 30% w/w, 52.0 mmol) was added to the reaction mixture. The resulting mixture was heated to 80° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature, and diluted with water (50 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to yield 4-tert-butylsulfonylbenzoic acid (2.2 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.59 (s, 1H), 8.18 (d, J=8.0 Hz, 2H), 7.94 (d, J=7.6 Hz, 2H), 1.25 (s, 9H); ESI-MS m/z calc. 242.1. Found 241.3 (M−1)−; Retention time: 1.33 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]2[O:15][CH:3]12)=[N:10][O:11][N:12]=3.[NH3:17].CCO>>[CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:17])[CH:3]1[OH:15])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C2OC21
Reactant: N
Solvent: CCO
Product: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Yield: 87 %

Procedure:
0.82 g (3.8 mmol) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole were dissolved in 25 ml of 16.7% NH3 -EtOH and reacted for at 60° C. for 48 hours in a pressure glass tube. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate-methanol=5:1) to obtain 0.77 g of the intended compound as a brown solid. (yield: 87%) A part of the product was recrystallized from ethanol to obtain pure colorless crystals of the intended compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:9][C@H:10]1[CH2:15][N:14]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=2)[N:21]=1
Reactant: O=Cc1ccncc1
Reactant: C[C@H]1CNCCN1c1ccc2nnc(C(F)(F)F)n2n1
Product: C[C@H]1CN(Cc2ccncc2)CCN1c1ccc2nnc(C(F)(F)F)n2n1
Yield: 53 %

Procedure:
A mixture of pyridine-4-carboxaldehyde and 6-[(2S)-2-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(2S)-2-methyl-4-(pyridin-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 53% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH3:21]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15]([NH2:21])[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CC1
Reactant: N
Solvent: CO
Product: COC(=O)C1CCC(c2cc(N)n3nccc3n2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
4-(7-Chloro-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexanecarboxylic acid methyl ester (2.5 g, 8.51 mmol) was dissolved in 15 mL ˜7N ammonia in methanol in a sealed vessel. The reaction mixture was heated at 80° C. for 16 hours. After 16 hours, the reaction mixture is cooled to room temperature and concentrated in vacuo to yield a brown solid (2.58 g). The title compound was used in the next step without further purification. LC-MS: 275 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C:42]([N:44]3[CH2:45][CH2:46][CH2:47][CH2:48]3)=[O:43])=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(C(=O)N3CCCC3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C(=O)N4CCCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 116A. MS (ES+): m/z 677.46 (100) [MH+]; HPLC: tR=0.98 min (UPLC, purity).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1.[C:17](O)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:9][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:8]
Reactant: CC(C)(C)O
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC(C)(C)C)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A mixture of 5-nitro-isophthalic acid monomethyl ester (D77) (5.0 g, 22.2 mmol, 1 equiv), tert-BuOH (8.2 g, 111 mmol, 5 equiv), EDAC.HCl (4.8 g, 25 mmol, 1.1 equiv) and DMAP (205 mg, 1.68 mmol, 0.07 equiv) dissolved in CH2Cl2 (50 ml) was stirred for 1 h at room temperature The mixture was then diluted with CH2Cl2 (50 ml), washed with 2N aqueous HCl solution (50 ml) and saturated aqueous NaHCO3 solution (50 ml), dried over MgSO4 and concentrated in vacuo to give of 5-nitro-isophthalic acid 1-tert-butyl ester 3-methyl ester (D78) (5.3 g, 85%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]=2[CH:14]=1.[H-].[Na+].I[CH2:18][CH3:19].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]=2[CH:14]=1
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2c(c3cc(Br)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A 500-mL round-bottomed flask was charged with 3-bromo-6,7,8,9-tetrahydro-5H-carbazole (5 g, 20.08 mmol, 1.00 equiv) in N,N-dimethylformamide (270 mL). To this solution was added sodium hydride (1.2 g, 30.00 mmol, 1.50 equiv, 60%) in several batches at −10° C., followed by addition of iodoethane (6.26 g, 40.13 mmol, 2.00 equiv) as a solution in N,N-dimethylformamide (30 mL) drop wise −10° C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC (EtOAc:PE=1:1). Upon completion, the reaction was then quenched by the addition of water/ice (120 mL). Then, the mixture was extracted with ethyl acetate (4×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1/20) affording 3-bromo-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole as brown oil (5 g, 90%).
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=1)[N:10]([CH3:21])[CH2:9][CH2:8]2.[C:22]([Br:25])(=[O:24])[CH3:23]>FC(F)(F)C(O)=O>[BrH:25].[C:22]([O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:3](=[O:2])[CH3:12])=[C:15]([O:20][C:16](=[O:19])[CH3:15])[CH:14]=1)[N:10]([CH3:21])[CH2:9][CH2:8]2)(=[O:24])[CH3:23]
Reactant: CN1CCc2cccc(O)c2C1c1ccc(O)c(O)c1
Reactant: CC(=O)Br
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C2c3c(cccc3OC(C)=O)CCN2C)cc1OC(C)=O

Procedure:
A mixture of 1.0 g of 8-hydroxy-1-(3,4-dihydroxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide prepared as in Example 4 above and 200 ml of trifluoroacetic acid is mixed with 1.3 ml of acetyl bromide. After heating at reflux for 2 hours, the mixture is evaporated to dryness. The residue is purified by recrystallization to give 8-acetoxy-1-(3,4-diacetoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide. Similarly isobutyryloxy, propionyloxy, isovaleryloxy, n-butylryloxy and n-heptanoyloxy derivatives are prepared.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](S(C)=O)=[N:6][N:7]=1.[CH3:13][O-:14].[Na+]>CO>[NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5]([O:14][CH3:13])=[N:6][N:7]=1
Reactant: C[O-]
Reactant: Cn1c(S(C)=O)nnc(N)c1=O
Agent: [Na+]
Solvent: CO
Product: COc1nnc(N)c(=O)n1C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4.1 g of 6-amino-4-methyl-3-methylsulfinyl-1,2,4-triazin-5-one are suspended in 50 ml of absolute methanol, and 4.3 ml of 30% strength methanolic sodium methylate solution are added at room temperature. The reaction proceeds slightly exothermically and the temperature rises to 35° C. The solution is then stirred at 50° C. for 30 minutes, whereupon a colourless precipitate separates out of the clear yellow solution. The reaction mixture is evaporated and the residue is taken up in ethyl acetate and ice-water. The organic phase is separated off, dried with magnesium sulfate and evaporated. The residue is washed with a little methanol and dried. 1.6 g of 6-amino-4-methyl-3-methoxy-1,2,4-triazin-5-one with a melting point of 198°-199° C. are obtained in this manner.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=[C:7]([CH2:9][O:10][Si](C(C)(C)C)(C)C)[N:8]=1)(=[O:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:4]1[N:5]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)cn1COC(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)c1nc(CO)cn1COC(=O)C(C)(C)C
Reaction time: 4 h
Yield: 106.3 %

Procedure:
2,2-Dimethylpropionic acid [2-acetyl-4-(tert-butyldimethylsilyloxymethyl)imidazol-1-yl]methylester (1.50 g) was dissolved in THF (50 mL), and at room temperature acetic acid (1 mL) and TBAF (1.0 M THF solution, 4.97 mL) were added, followed by stirring for 4 hours. The reaction solution was concentrated, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=100%→100%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (1.10 g).
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:39]=[CH:38][C:37]2[C@@H:36]3[C@H:27]([C@H:28]4[C@@:32]([CH2:34][CH2:35]3)([CH3:33])[C:31](=O)[CH:30]=[CH:29]4)[CH2:26][CH2:25][C:24]=2[CH:23]=1>O1CCCC1>[F:11][C:9]([F:10])=[C:31]1[CH:30]=[CH:29][C@H:28]2[C@H:27]3[C@H:36]([CH2:35][CH2:34][C@:32]12[CH3:33])[C:37]1[CH:38]=[CH:39][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH2:25][CH2:26]3
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(F)F)C=C[C@@H]12
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A solution of 9.4 g of diethyl-(difluoromethyl)-phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 5.6 g of 3-methoxy-estra-1,3,5(10),15-tetraen-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 6 hours. For working-up, half the volume is concentrated by evaporation in a vacuum, diluted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 3.0 g of 17-difluoromethylene-3-methoxy-estra-1,3,5(10),15-tetraene is obtained as colorless crystals with a melting point of 122-123° C., [α]D22 =-120.9° (c=0.515% in pyridine).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C[N:22](C)C=O>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:22])=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(Nc2ccncc2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(Nc2ccncc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-(4-Pyridinylamino)benzoic acid (43 g), 400 ml of thionyl chloride and 0.4 ml of dimethylformamide were mixed at 0° C. The mixture was heated on a steam bath for about 19 hours. The excess thionyl chloride was removed under reduced pressure and the residue azeotroped twice with toluene. The resulting acid chloride was suspended in 300 ml of acetonitrile. The suspension was cooled to 0° C. and an ice-cold solution of 0.8 ml of ammonia in 250 ml of acetonitrile was added dropwise over a period of 20 minutes. The reaction mixture was stirred for four hours and the solid material collected by filtration. The latter was slurried in 1 liter of water and 25 ml of saturated aqueous potassium carbonate was added. The solid product was collected and recrystallized twice from methanol to give 22 g of 4-(4-pyridinylamino)benzamide, m.p. 223°-226° C. A further recrystallization gave a sample with the m.p. 225.5°-227.5° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:29][CH2:30][CH2:31][CH2:32]Br)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCCN1CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reaction time: 8 h

Procedure:
5.00 g (12.44 mmol) of the compound from Example 20A are dissolved in 57 ml of acetonitrile, and 4.51 g (24.89 mmol) of 3-bromopropyl acetate and 3.44 g (24.89 mmol) of potassium carbonate are added. The reaction mixture is stirred at +80° C. for 8 h. After filtration, the solvent is removed on a rotary evaporator. The residue is taken up in 50 ml of ethyl acetate and washed in each case once with 10 ml of water and 10 ml of saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The crude product is used in the next reaction without further purification.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10][C@@H:2]12.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]2[CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10][C@@H:2]12.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@H]2NCCO[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (4aR,8aR)-6-benzyl 1-tert-butyl hexahydro-1H-pyrido[3,4-b][1,4]oxazine-1,6(7H)-dicarboxylate (388 mg, 1.03 mmol) dissolved in DCM (2.8 mL) was added TFA (0.57 mL). The reaction was stirred at room temperature for 16 hours. The mixture was concentrated to afford benzyl (4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as a TFA salt. MS ESI calc'd. for C15H20N2O3 [M+H]+ 277. found 277.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:33][N:32]=[C:31]([CH2:34][N:4]3[C:5]4[C:10](=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH:2]([F:1])[F:16])[N:30]=2)[CH:22]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:24]=1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ES) m/z 510 (M−1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 100 °C

Procedure:
To a sealed tube containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (Compound B-1) (1.24 g, 2.48 mmol) in 1,4-dioxane (20 mL) was added ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (1.12 g, 2.61 mmol) and Pd(PPh3)4 (0.87 g, 0.75 mmol). The mixture was flushed with N2, and was sealed and heated to 100° C. After 14 h of heating, the mixture was cooled to rt, was diluted with MeOH, and was filtered through a pad of celite to remove any solids. The solution was concentrated under reduced pressure, and was re-dissolved in DMF. The DMF solution was loaded on the prep HPLC for purification. After purification, the title product was isolated as an off-white solid (0.901 g). LCMS: m/e 559.6 (M+H)+, ret time 2.283 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.52 (s, 1H) 12.35 (s, 1H) 8.26-8.41 (m, 2H) 7.36-7.76 (m, 6H) 4.29-4.47 (m, J=6.71 Hz, 2H) 3.09-3.80 (m, 8H) 1.36 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:31])[CH2:26][CH2:27][C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[CH2:27][CH2:26][N:25]([CH3:31])[CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCN(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-dimethylamino propionic acid to yield (3aR,4S,7aR)-4-(3-dimethylamino-propionyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 413; RT 4.968 min; LC-MS Method ii
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[N:19]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:27]3[CH2:28][CH2:29][CH:24]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][CH2:26]3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Reactant: C1CCN(C2CCNCC2)C1
Product: CCc1cc(-c2cccc(CN3CCC(N4CCCC4)CC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with 4-pyrrolidinyl-piperidine as described in Method A, Example 123 to give the title compound. MS: m/e=381 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]([OH:19])=[O:18].[CH3:20]O>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CO
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Product: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 30 °C

Procedure:
A mixture of 3-methyl-5[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid (intermediate 130, 8.1 g) in methanol (300 ml) was heated at 30° C. and hydrogen chloride gas bubbled through the mixture. The reaction mixture was then stirred at reflux for 21 hours; cooled and treated with further hydrogen chloride gas. The reaction mixture was stirred at reflux for a further 6 hours, cooled and concentrated. The resulting precipitate was filtered and washed with cyclohexane to give the title compound as a solid.
Reaction SMILES: [CH2:1]([CH:3]([NH2:6])[CH2:4][CH3:5])[CH3:2].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:2][CH2:1][CH:3]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH2:4][CH3:5]
Reactant: O=S1(=O)CCCO1
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(CC)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-ethylpropylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 mL) was added a solution of 1,3-propane sultone (13.7 g, 110 mmol) in 20 mL of THF. The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×50 mL), and dried in vacuo., to afford compound DD (18.1, 80%): 1H NMR (D2O, 500 MHz) 8 ppm 3.08 (t, 2H, J=7.3 Hz), 3.01 (m, 1H), 2.87 (t, 2H, J=7.3 Hz) 2.00 (m, 2H), 1.59 (m, 4H), 0.82 (t, 6H, J=7.3 Hz). 13C NMR (D2O, 125 MHz) 8 ppm 60.87, 48.14, 43.68, 21.81. 21.60, 8.25. ES-MS 208 (M−1).