Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:17]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:7][C:6]=2[CH:17]=1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2cscc21
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3cc(Cl)ccc3Nc3cscc32)CC1

Procedure:
A solution of 0.9 g. of 7-chloro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 4.5 ml. of N-methylpiperazine is treated with 2-3 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled and made alkaline with concentrated ammonium hydroxide. The sticky precipitate is collected and dissolved in chloroform. The dried chloroform solution is concentrated under reduced pressure to give 7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine as an oil. An ethanolic solution of the oil is treated with 70% perchloric acid and diluted with water. The precipitate is recrystallized from methanol to give yellow crystals, m.p. 268°-270° C. (dec.).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br.O>C(O)(=O)C>[Br:19][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=1
Reactant: BrBr
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Solvent: CC(=O)O
Solvent: O
Product: Oc1c(Cc2ccccc2)cc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
A solution of 2-(phenylmethyl)-1-naphthol (1.00 g, 4.3 mmole) in acetic acid (20 mL) was stirred at room temperature. A solution of bromine (0.7 g, 4.3 mmole) in acetic acid (6 mL) was added dropwise over 10 minutes. The mixture was stirred for another 5 minutes, then poured into water. The resulting solid was collected by filtration and recrystallized (cyclohexane) to provide the title compound (1.21 g, 88%) as off-white needles, mp 123°-125°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:10]1([S:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:17][S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CSc1ccccc1)c1ccccc1O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Oc1ccccc1C(=CSc1ccccc1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. The resultant mixture was stirred for 30 minutes, followed by an addition of 2.10 g of 2-phenylthio-2'-hydroxyacetophenone. The thus-obtained mixture was stirred at room temperature for 2 hours. Ice water was then added to the reaction mixture, followed by its extraction with methylene chloride. The methylene chloride extract was then subjected to a post treatment in the same manner as in Example 10. The reaction product was separated by column chromatography, thereby obtaining 0.2 g of Isomer A (Compound 61) and 1.0 g of Isomer B (Compound 62) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-phenylthioethylene as colorless crystals respectively.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: Brc1ncccn1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(-c2ncccn2)cc1
Yield: 73.3 %

Procedure:
To a degassed suspension of 4-formylphenylboronic acid (100 mg), 2-bromopyrimidine (107 mg) and sodium carbonate (212 mg) in acetonitrile (2 ml)/water (2 ml) was added freshly prepared tetrakis(triphenylphosphine)palladium(0), (40 mg) and the mixture was refluxed under nitrogen, for 20 hrs. The cooled reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with iso-hexane/ethyl acetate (75:25) to afford the sub-title compound as a solid (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[O:40])[N:36]([CH3:38])[N:37]=1>O1CCCC1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[OH:40])[N:36]([CH3:38])[N:37]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(Cl)cnc21
Temperature: -20 °C
Yield: 29.5 %

Procedure:
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629, 0.19 g, 0.44 mmol) was dissolved in tetrahydrofuran (0.9 mL). The solution was, cooled to −20° C. 2M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise to the mixture, then stirred to −5° C. After the reaction was cooled to −20° C., 5-(3-chloro-benzylamino)-2-methyl-2 H-pyrazole-3-carbaldehyde (648, 0.050 g, 0.20 mmol) in 2 mL of tetra.hydrofuran was added at once to the mixture. The reaction was stirred to 0° C. and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hlexane gave the desired compound (649, 0.033 g, 30%). (ESI) [M+H+]+=558.3, 560.9.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]([C:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[O:14])=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:27]>CN(C=O)C>[CH3:12][O:11][C:9]([C:6]1[C:5]([C:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[O:14])=[CH:4][CH:3]=[C:2]([CH2:1][OH:27])[N:7]=1)=[O:10]
Reactant: COC(=O)c1c(C(=O)c2ccc3c(c2)OCO3)ccc(C)[n+]1[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1nc(CO)ccc1C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a DMF(15 ml) solution of 6-methyl-3-(3,4-methylenedioxyphenylcarbonyl)-2-methoxycarbonylpyridine N-oxide(1.56 g,4.95 mmol) was added anhydrous trifluoro acetic acid(7 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 h. After removal of the excess anhydrous trifluoro acetic acid the residue was partitioned between water and AcOEt. The organic layer was washed with a saturated aqueous solution of NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give 6-hydroxymethyl-3-(3,4-methylenedioxyphenylcarbonyl)pyridine-2-carboxylic acid methyl ester(1.72 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([OH:16])(=[O:15])=O)=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=1[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([NH:21][C:22]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=3[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])(=[O:16])=[O:15])=[CH:11][C:10]([C:17]([F:19])([F:20])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Reactant: O=S(=O)(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)C)c1NS(=O)(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 9 h
Yield: 9.8 %

Procedure:
To 2.84 g (10.2 mmol) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-sulfonic acid (i.e. the title material from Step C) in 70 mL of dichloromethane was added 1.96 g (10.2 mmol) of 2-amino-3-methyl-N-(1-methylethyl)benzamide (i.e. the title compound of Step E) 1.78 mL (10.2 mmol) of diisopropylethylamine and approximately 5 mg of 4-(dimethylamino)pyridine. The reaction mixture was stirred for 9 hours, then washed with water and dried (sodium sulfate). The solvent was removed with a rotary evaporator. The residue was purified by MPLC (20–40% ethyl acetate in hexanes as eluant) to afford 0.50 g of the title compound as a foamy white solid melting at 69–72° C. 1H NMR (CDCl3) δ 0.1.12 (d, 6H), 2.32 (s, 1H), 3.85 (m, 1H), 5.96 (brd, 1H), 7.07 (s, 1H), 7.35 (m, 3H), 7.39 (dd, 1H), 7.89 (dd, 1H), 8.20 (dd, 1H), 9.26 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[N:37]1([CH2:42][CH2:43][CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=[CH:38]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:45][CH2:44][CH2:43][CH2:42][N:37]3[CH:41]=[CH:40][N:39]=[CH:38]3)=[O:28])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: NCCCn1ccnc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCCn4ccnc4)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and 3-(1H-imidazol-1-yl)propylamine using diethyl cyanophosphonate as a coupling reagent Mass: 616.15 (M+H).
Reaction SMILES: ClC1C=C2C(=CC=1)N=C([N:12]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[C:23]=1[F:35])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)C=C2.Br[C:37]1[CH:46]=[C:45]([CH3:47])[C:44]2[C:39](=[C:40]([CH3:48])[CH:41]=[CH:42][CH:43]=2)[N:38]=1>>[CH3:47][C:45]1[C:44]2[C:39](=[C:40]([CH3:48])[CH:41]=[CH:42][CH:43]=2)[N:38]=[C:37]([N:12]([CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[C:23]=2[F:35])[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:46]=1
Reactant: Cc1cc(Br)nc2c(C)cccc12
Reactant: CCOc1cc(CN(c2ccc(C#N)cc2)c2ccc3cc(Cl)ccc3n2)c(F)c(OC(C)C)c1
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2cc(C)c3cccc(C)c3n2)c(F)c(OC(C)C)c1

Procedure:
According to the procedure for Intermediate 90.2, Intermediate 92.1 (100 mg, 0.424 mmol) afforded 97 mg of Intermediate 92.2 as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH2:21][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C1CCNCC1
Reactant: CCCCCCC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCCCCCC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 14 and piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][C:22]3[NH:23][CH:24]=[C:25]([CH2:29][CH3:30])[C:26](=[O:28])[N:27]=3)=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][C:22]3[N:23]([CH3:31])[CH:24]=[C:25]([CH2:29][CH3:30])[C:26](=[O:28])[N:27]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3cc(Cl)cc(C(F)(F)F)c3)cc2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2ccc(Oc3cc(Cl)cc(C(F)(F)F)c3)cc2)nc1=O
Yield: 14 %

Procedure:
The same procedure as E141 from 2-{[2-(4-{[3-chloro-5-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (100 mg, 0.228 mmol), DIPEA (0.099 mL, 0.570 mmol) and MeI (0.028 mL, 0.456 mmol) in DCM (2 mL), except that the reaction time was 3 h, to afford the title compound (18 mg, 0.032 mmol, 13.93% yield). LCMS: rt=3.68 min, [M+H]=453
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([N:41]3[CH2:42][CH2:43][CH:38]([C:29]4[CH:30]=[CH:31][C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:28]=4)[CH2:39][CH2:40]3)=[O:26])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc5ccccc5c4)CC3)cnc12
Yield: 48.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (120 mg, 0.33 mmol) obtained in Example 90, step 2 and 4-(2-naphthyl)piperidine hydrochloride (WO1997/037979, 100 mg, 0.40 mmol), the title compound (89 mg, 49%) was obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>ClCCl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][O:15][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred of 1-(4-trifluoromethyl-phenyl)-cyclopentyl]-methanol (239) (15 g, 61.47 mmol) in dichloromethane (200 mL) was added Et3N (17.1 mL, 123 mmol) followed by mesyl chloride (5.7 mL, 73.77 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched by the addition of water. The reaction mixture was diluted with dichloromethane. The organic part was washed with water, separated, dried over Na2SO4 and finally concentrated. The crude product was purified by 100-200 silica column chromatography using 10% ethyl acetate in hexane as the eluent to give methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240) (14 g, 70.6%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH:9](O)=[O:10]>>[CH:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:10]
Reactant: O=CO
Reactant: CC(C)[C@H](N)C(=O)O
Product: CC(C)[C@H](NC=O)C(=O)O
Reaction time: 17 h

Procedure:
To valine (11.7 g, 0.10 mol) in 88% formic acid (40 ml) is added acetic formylanhydride (26.3 g, 0.30 mol) over 0.5 hr at 5°. The reaction mixture is warmed to 24° and stirred for 17 hours. The reaction is worked up by distilling off (bath temp. 45°-50°) the solvent, excess anhydride and acetic acid, to give, as a white solid, N-formylvaline, recrystallized from hot ethanol, m.p. 143°-145°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]2[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pt]>[NH2:19][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:18][CH:17]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Yield: 94 %

Procedure:
tert-Butyl [4-(6-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate (17.62 g, 37.77 mmol) was dissolved in toluene (600 mL) with heating and added to a Parr vessel charged with 5% platinum on carbon (2.20 g). The vessel was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for three hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to provide 15.5 g of tert-butyl {4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate as a brown solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=2)[C:8]=1[Cl:32])C.[OH-].[K+].Cl>C1COCC1.O>[Cl:32][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)O)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
A mixture of [1-chloro-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.0701 g, 0.146 mmol) and potassium hydroxide (0.032 g, 0.57 mmoles) in THF (4 mL) and water (4 mL) was stirred for 1.5 hours at ambient temperature. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated dried in vacuo at 60° C. for 14 hours to yield [1-chloro-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid as a yellow semi-solid (0.0462 g, 69.9%); Mass spectrum (+ES, [M+H]+) m/z 453; 1H NMR (500 MHz, DMSO-d6): δ12.9–13.5 (br, 1H), 8.26 (d, 1H, J=8.85 Hz), 8.16 (d, 1H, J=1.83 Hz), 8.09–8.10 (m, 2H), 7.97–7.99 (m, 1H), 7.77 (dd, 1H, J=8.70 and 1.83 Hz), 7.47–7.56 (m, 3H), 5.03 (s, 2H), 2.43 (t, 2H, J=7.25 Hz), 1.42–1.48 (m, 2H), 0.98–1.06 (m, 2H), 0.59 ppm (t, 3H, J=7.40 Hz). Elemental Analysis for C25H21ClO4S+0.2 moles H2O: Calcd: C, 65.77; H, 4.72; N, 0.00; Found: C, 65.74; H, 4.99; N, 0.00.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22][CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].C([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[C:17]([O:22][CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14]=3[C@@H:26]2[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]2[CH2:32][OH:33])=[C:2]([Br:1])[CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc([N+](=O)[O-])cc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(N)cc3Br)oc2c1[C@@H]1CCN(C)[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound of example 41 (0.3 g, 0.6 mmol) was treated with iron dust (0.3 g) in water (1.2 mL) and glacial acetic acid (1.2 mL). The reaction mixture was stirred vigorously at room temperature for 1 h. It was poured into water (25 mL), basified using saturated aqueous Na2CO3 solution and extracted with EtOAc (3×25 mL). The organic extract was washed, dried (anhydrous Na2SO4) and concentrated to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CN)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine hydrochloride obtained by Example 70 (150 mg) and triethylamine (0.1 ml) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (0.06 ml) under ice cooling.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([N:34]2[C:38]([C:39]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)=[N:37][NH:36][C:35]2=[O:48])=[CH:25]1.[Br:49]C(Br)(Br)Br>C1COCC1>[Br:49][CH2:21][CH2:22][CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([N:34]2[C:38]([C:39]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)=[N:37][NH:36][C:35]2=[O:48])=[CH:25]1
Reactant: O=c1[nH]nc(-c2c[nH]c3ccccc23)n1-c1cn(CCCO)c2ccc(F)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2c[nH]c3ccccc23)n1-c1cn(CCCBr)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
Triphenylphosphine (0.168, 0.64 mmol) was added to a mixture of 4-[1-(3-hydroxy-propyl)-5-fluoro-indol-3-yl]-5-(1-H-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one (0.23 g 0.59 mmol), synthesised in accordance to the procedure for Example 1, triphenylphosphine (0.168 g, 0.64 mmol) and tetrabromomethane (0.218 g, 0.66 mmol) in dry THF (15 ml). The resulting mixture was stirred at ambient temperature. After 16 h the LCMS showed that some starting material still was left. Additional tetrabromomethane (0.198 g, 0,60 mmol) and triphenylphosphine (0.158 g, 0.60 mmol) were added and the solution was allowed to proceed for 20 h more at ambient temperature. Evaporation and silica gel chromatography (dichloromethane/methanol, gradient to 100/5) afforded 0.165 g (57%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:17])([F:18])[F:1])=[CH:7][C:8]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:22])=[O:21]
Reactant: COC(=O)Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: O=S(=O)(O)Cl
Product: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 2-(3-(2,2,2-trifluoroacetamido)phenyl)acetate (1.0 g, 3.8 mmol) at 0° C. was added ClSO2OH (2.3 g, 19.2 mmol). Then the mixture was stirred at room temperature for 2 hr. The mixture was poured into ice water and extracted with DCM. The combined organic layer were dried and concentrated to give the crude product methyl 2-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate. The product used directly to next reaction.