Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC(N1CCN(C2N=CC3C(=O)N(CC)C=C(C=O)C=3N=2)CC1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:32]>C(O)(=O)C>[BrH:32].[CH2:1]([Br:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1cc(C=O)c2nc(N3CCN(C(=O)OCc4ccccc4)CC3)ncc2c1=O
Agent: Br
Solvent: CC(=O)O
Product: BrCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolved in a 25% hydrogen bromide solution of acetic acid was 0.2 g of the 2-(4-benzyloxycarbonylpiperazino)-5,6-dihydro-6-ethyl-5-oxopyrido[4,3-d]pyrimidine-8-carbaldehyde obtained in Referential Example 20. The resulting mixture was stirred at room temperature for 1 hour. Hydrogen bromide, acetic acid and resulting benzyl bromide were distilled off under reduced pressure. After neutralizing the residue with a saturated aqueous solution of sodium carbonate, the mixture was extracted with chloroform and the chloroform layer was dried with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure to obtain 0.13 g of light yellowish crystals (yield: 95%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10](Br)[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].[Br-].[CH2:14]([Zn+])[CH2:15][CH3:16]>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH2:15][CH3:16])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Reactant: CCC[Zn+]
Agent: [Br-]
Product: CCCc1cc(C=O)cc(C(=O)O)c1

Procedure:
The title compound is prepared in analogy to 3-formyl-5-ethyl-benzoic (582 mg) from 3-formyl-5-bromo-benzoic acid (1.00 g, 4.37 mmol) using propyl zinc bromide. LC-MS*: tR=0.56 min, [M−H]−=191.32; 1H NMR (D6-DMSO): δ 0.91 (t, J=7.3 Hz, 3H), 1.65 (h, J=7.3 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H), 7.97 (s, 1H), 8.07 (s, 1H), 8.28 (s, 1H), 10.07 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]3[N:16]=[C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:22][CH:21]=4)[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6]1.[OH-].[Na+]>CO>[N:29]1([CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:17]3[N:18]=[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH2:4][C:3]([OH:34])=[O:2])[CH:9]=5)[N:15]4[N:16]=3)=[CH:21][CH:22]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-acetic acid methyl ester (0.51 g, 1.11 mmol) in methanol (10 ml) was added sodium hydroxide (2N, 1 mL) and the mixture stirred for 3 hours at room temperature. All solvents were removed in vacuo to afford the title compound as a pale yellow solid. No further purification was required. Yield: 0.40 g, 80%; LCMS method: 2, RT: 2.36 min, MI: 448 [M+1].
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([O:12]C(=O)C)[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Oc1cccc(OC2CCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cccc(OC2CCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.7 %

Procedure:
Acetic acid 3-cyclobutoxy-phenyl ester (340 mg, 1.65 mmol) was dissolved in methanol (6 ml) and 1 M sodium hydroxide solution (2 ml, 2 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours and then was acidified with 2 M hydrochloric acid. The reaction mixture was extracted with ethyl acetate and the organic solution was dried over magnesium sulphate and concentrated in-vacuo to give 3-cyclobutoxy-phenol (300 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C([Li])CCC.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCC1
Reactant: c1cocn1
Agent: B
Agent: [Li]CCCC
Product: OC1(c2ncco2)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
An ambient solution of oxazole (1.00 g, 14.5 mmol) and borane●tetrahydrofuran complex (14.5 mL, 14.5 mmol, 1 M in tetrahydrofuran) was stirred for 30 min. The reaction was cooled to −78° C., and n-butyllithium (9.5 mL, 15.2 mmol, 1.6 M in hexane) was added dropwise. After 30 minutes, cyclopentanone (1.42 mL, 16.0 mmol) was added dropwise. After 30 minutes, the cold (−78° C.) reaction was quenched by the addition of 5% acetic acid in ethanol (70 mL) and warmed to room temperature. The solution was diluted with diethyl ether (10.0 mL) and saturated NaHCO3 (50 mL). Layers were separated, and the organics were washed with brine (1×50 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.71 (m, 2 H), 1.72-1.84 (m, 2 H), 1.84-1.96 (m, 2 H), 1.98-2.09 (m, 2 H), 5.40 (s, 1 H), 7.11 (s, 1 H), 8.02 (s, 1 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17]>O1CCCC1.C(O)C>[NH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[C:16]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:17]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To an ice-cold solution of 28 ml (134 mmol) of 4-amino-1-(phenylmethyl)piperidine in 200 ml of tetrahydrofuran were added, batchwise, 21.9 g (134 mmol) of isatoic acid anhydride. The resulting suspension was stirred for 2½ hours at room temperature and 2½ hours at reflux temperature, then freed from solvent. The residue was dissolved in 100 ml of hot ethanol, the resulting solution was filtered whilst hot after the addition of 5 g of activated charcoal. The crystal mass precipitated after cooling was suction filtered, washed with diisopropylether and dried in vacuo at 50° C. 28.3 g of colourless crystals were obtained. A further 5.1 g of a product of the same quality were isolated from the combined mother liquors. Total yield: 33.4 g (80.6% of theory).
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:4]=[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]2[CH:16]=1>C(O)C.CN(C)C1C=CN=CC=1>[CH2:11]([O:12][CH:2]([O:13][CH2:14][CH3:15])[C:3]1[N:4]=[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]2[CH:16]=1)[CH3:10]
Reactant: CCOC(=O)c1cccn2cc(C(Cl)Cl)nc12
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1cccn2cc(C(OCC)OCC)nc12
Temperature: 25 °C
Yield: 194.4 %

Procedure:
To a solution of dichloro compound 2h (1.00 g, 3.66 mmol) in dry ethanol (100 mL), under argon, was added 4-dimethylaminopyridine (DMAP) (0.90 g, 7.38 mmol). The solution was stirred under reflux for 20 h. After cooling to room temperature, the solution was concentrated under vacuo. The resulting precipitate was suspended in ethyl acetate (30 mL), filtered and washed with AcOEt (3×10 mL). The filtrate was evaporated to dryness. The crude product was chromatographed using AcOEt/cyclohexane (8/2, v/v) as eluent to afford compound 2i (1.04 g, 97%). Ketal compound 2i (0.30 g, 4%); mp 98-100° C.; IR (KBr) 1716, 1267, 1166 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 6H, J=7 Hz), 1.41 (t, 3H, J=7 Hz), 3.68 (m, 4H), 4.46 (q, 2H, J=7 Hz), 5.81 (s, 1H), 6.85 (t, 1H, J=7 Hz), 7.78 (s, 1H), 7.90 (d, 1H, J=7 Hz), 8.32 (d, 1H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 14.3, 15.3, 61.6, 62.3, 99.0, 111.0, 111.5, 120.2, 128.9, 129.8, 142.0, 146.3, 164.2. MS m/z 293 (M++1, 1), 248 (22), 219 (100), 191 (17), 173 (52), 146 (18) 117 (13).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[CH:25]=1)=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[CH:25]=1)=[O:23]
Reactant: CNC(=O)c1cn(C)c2cc(O)ccc12
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1cn(C)c2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b with 6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.53 (1H, d, J=5.5 Hz), 8.25 (1H, d, J=8.7 Hz), 7.96 (1H, d, J=6.2 Hz), 7.86 (1H, s), 7.46 (1H, d, J=1.9 Hz), 7.12 (1H, d, J=8.5 Hz), 6.74 (1H, d, J=5.5 Hz), 4.19–4.11 (1H, m), 4.05–3.95 (2H, m), 3.38 (3H, s), 3.85–3.72 (2H, m), 3.40 (3H, d, J=13.9 Hz), 2.96 (3H, s), 2.30–2.09 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 465. found 465. Anal. (C24H24N4O4S.0.4CH2Cl2) C, H, N.
Reaction SMILES: [N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O1CCCC1.[Pd]>[N:1]1[C:11]2[C:10]3[S:12][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][NH2:22])=[N:19][CH:20]=4)=[CH:14][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1

Procedure:
A solution of 25 mg (0.082 mmol) of 5-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)pyridin-2-nitrile in 3 ml of acetic acid and 3 ml of tetrahydrofuran was subjected to hydrogenation over 40 mg of 5% palladium on charcoal for 4 hours. The catalyst was filtered off, the mother liquor was concentrated in vacuum. The residue was triturated with ethyl ether afforded a precipitate which was collected and dried in vacuum to give 319. Yield 24 mg (79%). MS: (ESI+) 310.0. 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.25 (dd, J=4.4, 1.1, 1H), 8.06 (dd, J=8.1, 1.9, 1H), 7.50 (d, J=9.9, 2H), 7.42 (dd, J=8.1, 1.1, 1H), 7.23 (dd, J=8.1, 4.5, 1H), 4.35 (t, J=4.6, 1H), 3.86 (s, 2H), 3.24 (t, J=4.6, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH2:22](Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH3:22])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(2S)—N-(tert-Butoxycarbonyl)-3-(pyridin-3-yl)alanine (25.00 g, 93.88 mmol) is dissolved in 300 ml of dichloromethane under argon. Methanol (11.4 ml, 9.02 g, 281 mmol, 3 equivalents) and one grain of DMAP are added. The mixture is then cooled to 0° C. EDC (19.80 g, 103 mmol, 1.1 equivalents) is added. After 5 min, the ice bath is removed and the mixture is left to stir at RT over 1 h. The mixture is then concentrated in vacuo, and ethyl acetate is added to the residue and the mixture is extracted against a saturated sodium hydrogen carbonate solution. The aqueous phase is reextracted once with ethyl acetate, then the combined organic phases are washed with 0.5 M citric acid and then once again with a saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. An oil remains, which crystallizes during drying in an oil-pump vacuum. Yield: 23.60 g (90% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]5)=[CH:17][CH:18]=4)C[CH2:12][C:11]=3[CH:10]=2)[O:3]1.BrC1C=CC2C3C(=CC(Br)=CC=3)CC=2C=1>>[CH3:1][C:2]1([CH3:32])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:22]=[CH:21][C:20]3[C:19]4[C:14](=[CH:15][C:16]([B:23]5[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:30])([CH3:31])[O:24]5)=[CH:17][CH:18]=4)[CH2:12][C:11]=3[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C
Agent: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: CC1(C)OB(c2ccc3c(c2)Cc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)OC1(C)C

Procedure:
Followed the procedure used to prepare 4,4,5,5-tetramethyl-2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl]-[1,3,2]dioxaborolane, except that 2,7-dibromofluorene was used instead of 2,7-dibromo-9,10-dihydro-phenanthrene. 1H-NMR (300 MHz, CDCl3) δ 8.01 (s, 2H), 7.84 (s, 4H), 3.90 (s, 2H), 1.38 (s, 24H).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][NH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:12]1=[O:40])C.[OH-].[Na+:49].O>O>[Na+:49].[F:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:16](=[O:17])[N:11]([CH2:10][C@H:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([O-:47])=[O:3])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:12](=[O:40])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:14]=1[CH3:27]
Reactant: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC(=O)[O-])c3ccccc3)c2=O)c1F
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a reactor was charged a solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a from the previous step. Reagent alcohol (6.0 L) was added and the temperature adjusted to 20° C. A solution of NaOH/water (440 g/6.0 L) was added and the reactor contents were stirred at 20-25° C. for two hours until reaction completion. Water (9.0 L) was added and the reactor contents were concentrated using vacuum distillation to a volume of approximately 15.0 L. Water (15.0 L) and methyl isobutyl ketone (9.0 L) was charged, the mixture was agitated, the layers were separated, and the aqueous layer was retained. A second wash with methyl isobutyl ketone may be performed if needed. Methyl isobutyl ketone (9.0 L) was added and the mixture concentrated by vacuum distillation to a volume of approximately 30 L and ethanol content less than 3%. The reactor contents were set to a temperature of 25-30° C. and sodium chloride (4507 g) and methyl isobutyl ketone (21.0 L) were charged to the reactor and agitated. The layers were separated and the organic layer was concentrated to ˜2-3 volumes methyl isobutyl ketone. The concentrated solution was filtered through Celite and a 0.3 μm line filter. The filtered solution was charged to a well-agitated reactor containing heptane (30.0 L) cooled to 10-20° C. The mixture was stirred for two hours, filtered, and the cake was washed with heptane (8 L). The product was dried in a vacuum oven for 24-48 hr at 70-75° C. to provide 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid sodium salt 5-1 as an off-white solid (2.46 kg, 64% yield). LCMS (ESI) m/z 632.2 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]2[NH:7][C:8]([C:10]([C:19]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4C(OC(C)(C)C)=O)([NH:15][CH2:16][CH2:17][OH:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+]>CO>[F:13][C:11]([F:12])([F:14])[C:10]([C:8]1[NH:7][C:6]2[CH:38]=[CH:39][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([NH:15][CH2:16][CH2:17][OH:18])[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NCCO)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(NCCO)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-((2-hydroxyethyl)amino)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (20 mg, 0.037 mmol) in MeOH (0.368 mL) at room temperature under nitrogen, Cs2CO3 (59.9 mg, 0.184 mmol) was added and the reaction was stirred at 60° C. After 90 minutes the reaction was cooled, quenched with NH4Cl, extracted with EtOAc, dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48-12.70 (m, 1H) 10.99 (br. s., 1H) 8.27 (m) 7.89 (m) 7.81 (m) 7.56 (dd, J=8.34, 1.52 Hz, 1H) 7.48 (m) 7.06-7.21 (m, 1H) 6.81 (s, 1H) 6.01 (br. s., 1H) 4.48 (t, J=5.24 Hz, 1H) 3.34-3.54 (m, 5H) 2.56-2.72 (m, 1H) 2.46 (s, 3H) 2.01 (br. s., 1H). HRMS calcd. for C22H20F3N5O2 (M+H)+ 444.1647. found 444.1656.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=2)[CH:7]=1.O.[NH2:17][NH2:18]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:17][NH2:18])=[O:13])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cnc2ccc(Br)cn12

Procedure:
A mixture of 1.94 g ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate, 6 mL hydrazine monohydrate and 20 mL ethanol was heated for 1 hour under reflux. The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure by a vacuum pump to give 1.71 g of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1>C(N)C1C=CC=CC=1>[CH2:19]([NH:20][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: CCC(O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Solvent: NCc1ccccc1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(NCc4ccccc4)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (100 mg, 0.22 mmol) in benzylamine (0.3 mL) was stirred at 125° C. for 6 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound. MS (+ESI): 536 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 66 mg (0.56 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 77 mg (42% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([SH:22])[CH:19]=[CH:20][CH:21]=1>C(O)C.[O-]CC.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][S:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Sc1cccc(Cl)c1
Reactant: C=C(C(=O)OCC)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(CSc1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of the ethyl 4-chlorophenyl-α-methyleneacetate (4.2 g), m-chlorothiophenol (2.9 g) and sodium ethoxide (0.05 g) in ethanol (20 ml) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water (150 ml) to the residue, and the mixture was extracted with ether (150 ml). The extract was washed two times with 15% aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the resulting residue were added 88% formic acid (20 ml) and methanesulfonic acid (2.1 ml), followed by heating at reflux for 8 hours. After cooling to room temperature, the mixture was poured into water (100 ml) and extracted with dichloromethane (150 ml). The aqueous layer was further washed with dichloromethane (50 ml), and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was subjected to chromatography on silica gel to give 4-chlorophenyl-α-[(3-chlorophenyl)thiomethyl]-acetic acid (yield, 5.3 g), nD23.6, 1.5627
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:38]=[C:9]2[C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[C:11]([CH3:27])[C:12]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[CH:13][N:8]2[N:7]=1)=[O:4].[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1>>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:14]([C:12]3[C:11]([CH3:27])=[C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[C:9]4[N:8]([N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:39]5[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]5)[N:38]=4)[CH:13]=3)=[CH:18][CH:17]=[N:16]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN3CCS(=O)(=O)CC3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chloro-N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 17, 50 mg, 0.0934 mmol) and thiomorpholine 1,1-dioxide (20 mg, 0.148 mmol) using a similar method to that employed for Example 18, Step 2 (10 mg).