Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH:14]1([C:20](OC)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:20](=[O:21])[CH2:1][C:2]#[N:3])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C1CCCCC1
Reactant: CC#N
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC1
Reaction time: 0.08 h

Procedure:
A solution of 0.53 mL (10 mmol) of MeCN in 5 ml of THF was cooled in −78° C. bath and 12 mL of 1M LiN(TMS)2 was added. After 5 min, 0.75 mL (5.2 mmol) of methyl cyclohexane carboxylate was added. The cold bath was removed after 1 hr and stirring was continued for another 1 hr. The reaction was acidified with 1.2 N HCl and extracted with ether. The ether layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-50% EtOAc-hexane to furnish the desired product.
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH3:15])[CH2:8][CH2:9]OS(C)(=O)=O)(=O)=O.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].O>[CH3:15][C@@H:7]1[CH2:8][CH2:9][N:16]([C@@H:17]([CH3:20])[CH2:18][OH:19])[CH2:6]1
Reactant: C[C@H](N)CO
Reactant: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
(R)-2-Methylbutane-1,4-diyl dimethanesulfonate (37.5 g, 0.144 mol) was added to neat (S)-2-aminopropan-1-ol (54.8 g, 0.730 mol). The mixture was stirred in a room temperature water bath to minimize the exotherm. After 24 h, the reaction was diluted with DCM (150 mL), sat'd K2CO3 solution (150 mL), and just enough water (60 mL) to dissolve the resulting ppt. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give (S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (17.9 g) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (t, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 2.79 (dd, 1H), 2.58 (m, 1H), 2.48 (m, 1H), 2.26 (m, 1H), 2.08 (m, 1H), 2.01 (dd, 1H), 1.88 (m, 1H), 1.20 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H); LCMS: 144.3 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:22])=[C:18](F)[CH:19]=2)[C:14](=[O:23])[C:13]([C:24]([OH:26])=[O:25])=[CH:12]1)[CH3:10]>N1C=CC=CC=1>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:22])=[C:18]([N:7]3[CH2:6][CH2:5][NH:4][CH:3]([CH2:2][F:1])[CH2:8]3)[CH:19]=2)[C:14](=[O:23])[C:13]([C:24]([OH:26])=[O:25])=[CH:12]1)[CH3:10]
Reactant: FCC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)cc21
Temperature: 75 °C
Yield: 36 %

Procedure:
A mixture of 400 mg of 2-(fluoromethyl)piperazine and 200 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 3 ml of pyridine was stirred and heated at 75° C., under nitrogen, in a pressure bottle for 3 hours. The pyridine was removed and replaced with methanol. This mixture was chromatographed on silica gel, eluting with methanol:chloroform (2:8). The solid was recrystallized from methanol, giving 100 mg of the desired product, mp 177°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10](C)C(Cl)=O.C[Si](C#N)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: N#Cc1ncccc1Cl
Temperature: 25 °C
Reaction time: 240 h
Yield: 59 %

Procedure:
A 2M solution of 3-chloropyridine 1-oxide (C125) (10 mL, 20 mmol) is combined with an additional 90 mL of CH2Cl2. Dimethylcarbamoyl chloride (2.03 mL, 22.0 mmol) is added drop-wise, followed by the addition of trimethyl silylcyanide (2.93 mL, 22.0 mmol) via syringe. The reaction stirred at rt for 10 days and is quenched with 10% K2CO3 (100 mL). The layers are allowed to separate, and the organic layer is dried over K2CO3, filtered, and concentrated to an orange solid. The crude material is chromatographed over 160 g slurry-packed silica eluting with 40% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to yield 3-chloropyridine-2-carbonitrile (C126) as a white solid (59% yield). MS (EI) for C6H3ClN2, m/z: 138 (M)+.
Reaction SMILES: C(O)C.C([NH:11][C:12]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]2[C:13]=1[C:14](=[O:41])[C:15]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:16][N:17]2[C:25]1[CH:30]=[C:29]([NH:31][CH:32]=[O:33])[C:28]([F:34])=[CH:27][C:26]=1[F:35])C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:11][C:12]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]2[C:13]=1[C:14](=[O:41])[C:15]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:16][N:17]2[C:25]1[CH:30]=[C:29]([NH:31][CH:32]=[O:33])[C:28]([F:34])=[CH:27][C:26]=1[F:35]
Reactant: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(F)c(F)c(F)c(N)c2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
To 20 ml of ethanol and 10 ml of acetic acid were added 600 mg of ethyl 5-benzylamino-6,7,8-trifluoro-1-(2,4-difluoro-5-formylaminophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate and 100 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred at room temperature for 2 days. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 420 mg of the title compound.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:20]([N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(N3CCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.82 g (18.0 mmol) NaBH(OAc)3 are added to a solution of 1.23 mL (15.0 mmol) pyrrolidine and 2.41 mL (15.0 mmol) N-benzylpyrrolidinone in 100 mL THF and acidified with 2 mL acetic acid. The reaction is stirred overnight at RT. The reaction solution is combined with 200 mL saturated NaHCO3 solution and extracted twice with 200 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+].C(OCC)C>CN(C)C=O>[CH3:18][S:15]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][S:21][C:19](=[O:22])[CH3:20])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SCc1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Yield: 98.6 %

Procedure:
A solution of 4′-bromomethyl-3-methylsulfonylbiphenyl (190 mg, 0.57 mmol) (WO 01/70753) and potassium thioacetate (78 mg, 0.68 mmol) in N,N-dimethylformamide (4 mL) was heated at 150° C. in a microwave for 3 min. The reaction mixture was poured into diethyl ether (30 mL) and washed with water (3×15 mL), brine (15 mL), dried with magnesium sulfate, filtered, and concentrated to give a crude yellow oil. The crude oil was purified by flash column chromatography to yield 1.35-A (180 mg, 89%) as a thick light yellow oil. LCMS found for C16H17O3S2 (M+H)+: m/z=321.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)(Cl)Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:15]
Reactant: Cc1cc(C(=O)O)cc([N+](=O)[O-])n1
Reactant: CCNCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc(C)nc([N+](=O)[O-])c1

Procedure:
To a mixture of 1.0 g. of 6-methyl-2-nitroisonicotinic acid, 20 ml. of chloroform and 3 ml. of diethylamine was added 7.0 g. of phosphorus pentoxide with stirring. The resulting mixture was refluxed for 1 hour. After cooling, the chloroform layer was separated and poured into 20 ml. of water. The resulting mixture was neutralized with sodium hydrogencarbonate and the chloroform layer was separated, dried over anhydrous sodium sulfate and the chloroform was distilled off in vacuo. The residual oil was gradually crystallized and then recrystallized from ethyl acetate-n-hexane to give 0.6 g. of the desired product.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2>CN1CCCC1=O.O.Cl.[Fe](Cl)(Cl)Cl>[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)#[N:3]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2cc(O)ccc2c1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
Copper (I) cyanide (2.73 g, 0.03 mol) was added to a solution containing 5 g (0.022 mol) 6-bromo-2-hydroxynaphthalene in 25 ml of dry N-methyl-2-pyrrolidinone and refluxed at 200° C. under nitrogen for 1.5 h. The reaction mixture was cooled to 100° C., poured into a solution of iron(III) chloride (5.9 g) in water (91 ml) and concentrated hydrochloric acid (3.18 ml), and stirred at 60° C. for 30 min. The obtained mixture was extracted with ethyl ether. The ether layer was treated with charcoal, dried over anhydrous sodium sulfate, and then evaporated to dryness. The obtained solid was recrystallized from water to yield 2.04 g (54%) white solid. 1H-NMR (CDCl3, TMS, δ in ppm): 5.60 (s, 1H, --OH), 7.10-8.07 (m, 6, aromatic protons).
Reaction SMILES: ClC([O:4][CH:5]1[CH:12]2[CH2:13][CH:8]3[CH2:9][CH:10](C[CH:6]1[CH2:7]3)[CH2:11]2)=O.C1(CC[NH2:23])C=CC=CC=1>>[NH2:23][C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][OH:4]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: NCCc1ccccc1
Product: N[C@H](CO)Cc1ccccc1

Procedure:
The acid 6 is condensed with amines such as illustrated in Scheme X to produce final products, for example, condensation of 6 with phenylethylamine gives compound 13a with (S)-(-)-2-amino-3-phenyl-1-propanol gives compound 13b and with (R)-4-[[(2-amino-1-phenyl)ethyl]amino]-4-oxobutanoic acid benzyl ester to give 13c and 13d.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:46]=[CH:45][C:38]([C:39]([NH:41][CH:42]2[CH2:44][CH2:43]2)=[O:40])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:36]=[CH:37][C:38]([C:39](=[O:40])[NH:41][CH:42]3[CH2:44][CH2:43]3)=[CH:45][CH:46]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CC1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1CC1)c1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 4-bromo-N-cyclopropyl-benzamide (39.7 mg, 0.17 mmol), and Pd[P(Ph)3]4 (13.7 mg, 7.2 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.3 mg. MS: 484.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.51-0.70 (m, 4H), 1.76-1.98 (m, 3H), 2.08-2.30 (m, 1H), 2.77-2.86 (m, 1H), 3.38-3.52 (m, 2H), 4.27-4.37 (m, 1H), 4.86-5.08 (m, 2H), 6.96-7.65 (m, 7
Reaction SMILES: CC([O:5][C:6](=[O:32])[CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:31])[C:17]=2[NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:12]=1)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:16]1[C:17]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([OH:32])=[O:5])[CH:20]=[CH:19]2
Reactant: CC(C)(C)OC(=O)CCCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Reaction time: 3 h
Yield: 11.4 %

Procedure:
4-[[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]amino]-butanoic acid 1,1-dimethylethyl ester (Example 7 (a)) (200 mg) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and the mixture stirred for 3 hours. The resultant suspension was evaporated to dryness and recrystallised from acetonitrile to give the title compound (20 mg).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[F:41][C:42]1([F:46])[CH2:45][NH:44][CH2:43]1>C(#N)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:44]4[CH2:45][C:42]([F:46])([F:41])[CH2:43]4)=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])(=[O:15])=[O:16])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 396c) was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 55° C. for 48 h to give the title compound as colorless foam. MS (ESI): m/z=643.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[CH:10]=[CH:9][C:8]=2[OH:23])=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[C:32](F)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:39])=[O:38])[CH:36]=1>CS(C)=O>[Cl:30][C:31]1[C:32]([O:23][C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[N:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:38])=[O:39])[CH:36]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)nc2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)nc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
2-(Pyridazin-4-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)phenol (Preparation 59, 360 mg, 1.134 mmol) was dissolved in DMSO (6 mL) and potassium carbonate (313 mg, 2.27 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 524 mg, 1.134 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage (20% to 100% EtOAc in heptane over 20 CV) to give the title compound (501 mg, 58%) as yellow foam.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:26])[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccccn3)cc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccccn3)cc12
Reaction time: 22 h

Procedure:
A solution of 0.170 gm (0.0005 mol) of 4-methyl-6-[4-(2-pyridyl-mercapto)-butoxy]-carbostyril in 5 ml of glacial acetic acid and a solution of 0.107 gm (0.0005 mol) of sodium metaperiodate in 6 ml of water were admixed and allowed to stand at room temperature for 22 hours. Subsequently, the light brown reaction solution was diluted with 20 ml of water, and the reaction product was extracted with chloroform. The extract was shaken once with an aqeuous sodium carbonate solution and dried over anhydrous magnesium sulfate. After evaporating the organic phase, the residue was recrystallized from toluene.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:3]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5]
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(N)cc(C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-Bromo-2-iodo-5-(trifluoromethyl)aniline (18.7 g, 51.1 mmol) was dissolved in triethylamine (400 mL). To this was added dichlorobis(triphenylphosphine)palladium(II) (3.59 g, 5.11 mmol), copper(I) iodide (0.973 g, 5.11 mmol), and trimethylsilylacetylene (5.52 g, 56.2 mmol). The reaction was stirred for 2 h at ambient temperature, at 80° C. for 2 h, and then evaporated. The residue was purified by chromatography on silica gel with 5% ethyl acetate/hexanes to give 10.67 g (62.1%) as a brown liquid. 1H-NMR (CDCl3, 400 MHz) δ 7.13 (s, 1H), 6.82 (s, 1H), 4.52 (bs, 2H), 0.29 (s, 9H); LC/MS (HPLC method 4): tR=4.208 min, 336.05(MH)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:14])[CH:12]2[CH:7]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][CH2:4]1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)C>O1CCCC1>[Si:15]([O:14][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]2[CH:12]1[CH2:11][CH2:10][CH2:9][CH:8]2[OH:13])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCCC2C(O)CCCC12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CCCC2C(O)CCCC12
Temperature: 56 °C
Reaction time: 8 h

Procedure:
A suspension of 0.45 gm (12 mmole) of sodium hydride dispersion (60%) in 75 mL of tetrahydrofuran was treated with 2.0 gm (12 mmole) of 1,5-decalindiol in an inert atmosphere. This mixture was stirred overnight at about 56° C. then cooled to room temperature and 1.8 gm (12 mmole) of t-butyldimethylsilyl chloride added. The mixture was stirred at room temperature for 4 days then 200 mL of diethyl ether added followed by washing the resulting mixture with 10% aqueous potassium carbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was subjected to flash chromatography on 40 microns silica gel to give 5-(t-butyldimethylsilyloxy)-1 -hydroxydecalin as a clear, colorless oil. Satisfactory ir, cmr and pmr spectra were obtained.
Reaction SMILES: [Br:1]Br.[C:3]([O:9][C:10]1[CH:11]=[C:12]([C:23](=[O:25])[CH3:24])[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].C(OC(C)(C)C)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[Br:1][CH2:24][C:23]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:10]([O:9][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:11]=1)=[O:25]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)CBr)cc1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (3.15 ml., 0.061 mole) in chloroform (50 ml.) was added dropwise at room temperature to a stirred solution of 3',4'-bis(pivaloyloxy)acetophenone (19.5 g., 0.016 mole) and t-butyl acetate (8.2 ml., 0.06 mole) in chloroform (150 ml.) containing a catalytic amount of anhydrous aluminium chloride (0.2 g.). The reaction mixture was stirred at room temperature for 1 hour after the addition was complete, chromatographic silica gel (75 g.) was then added and the mixture evaporated in vacuo. The residual solid was added to the top of a column of dry chromatographic silica-gel (1 kg., previously deactivated by addition of 10% w/w water and then equilibrated with 10% v/w of a 5% v/v solution of ethyl acetate in toluene). The column was developed by elution with a 5% v/v solution (1.1 l.) of ethyl acetate in toluene. The column was then eluted with ethyl acetate (2×500 ml.) and the fractions collected were monitored by thin layer chromatography (TLC) (on silica plates developed in a 50% v/v mixture of ethyl acetate and toluene). The later fractions were combined and evaporated to give 2-bromo-3',4'-bis(pivaloyloxy)acetophenone as an oil (14.2 g.) which rapidly crystallised to give a solid of m.p. 64°-66° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:2][C:1](=[O:3])[CH2:4][CH2:5][C:6]1[C:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)[CH3:22]
Reactant: CCO
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1c[nH]c2c1C(=O)CCC2
Yield: 99 %

Procedure:
3-Carboxyethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (3, 52.0 g, 0.251 mol) in ethanol (100 mL) was added with sulfuric acid (1.0 mL). The reaction mixture was heated at reflux for 12 h. The solution was concentrated under reduced pressure and the resultant solids were washed with water (200 mL×2). The solids were air-dried to give 3-(3-ethoxy-3-oxopropyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole (4, 59.0 g, 0.251 mol) as yellow solids in >99% yield.