Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26]([OH:28])=O)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.[CH3:33][N:34]1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH3:33][NH:34][C:26]([C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([CH:7]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:29][C:21]2=[N:22][CH:23]=1)=[O:28]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 30.8 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (prepared as in Example 3, 200 mg, 0.48 mmol) and methylamine hydrochloride (39.4 mg, 0.58 mmol) in dichloromethane (1 mL), N,N-dimethylformamide (500 μL) and N-methylmorpholine (152 μL, 1.45 mmol) was added 1-hydroxybenzotriazole hydrate (132 mg, 0.97 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (186 mg, 0.97 mmol) in one portion. The mixture was then stirred at 25° C. for 14 h. The mixture was diluted with ethyl acetate (100 mL), washed with a 1 N sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methylamide (63 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C23H27N3O3S [M+H]+ 426.55, observed 426.4; 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (m, 2H), 1.49 (m, 2H), 1.55-1.84 (m, 5H, H), 2.10 (m, 1H), 2.23 (m, 1H), 3.02 (s, 3H), 3.07 (d, J=4.8 Hz, 3H), 4.23 (t, J=8.0 Hz, 1H), 6.36 (q, J=4.8 Hz, 1H), 6.42 (s, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 8.21 (d, J=2.1 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H), 10.89 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.[CH3:16][O:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20]>>[CH3:16][O:17][C:18](=[O:22])[C@H:19]([NH:20][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])[CH3:21]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Product: COC(=O)[C@@H](C)NC(=O)c1nc(Cl)c2ccccc2c1O

Procedure:
1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.55 g, was coupled with 0.40 g of D-Alanine methyl ester analogously to Example A-54 a) and 0.200 g of off-white, solid product were obtained: MS-(+)-icon, M+1=308.8 amu.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([CH2:7][N:8]1[C:12](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][C:19]\2=[O:20])=[CH:11][N:10]=[N:9]1)=[O:6]>O1CCCC1>[CH3:3][O:4][C:5]([CH2:7][N:8]1[C:12](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18][CH:19]\2[OH:20])=[CH:11][N:10]=[N:9]1)=[O:6]
Reactant: COC(=O)Cn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 29.1 %

Procedure:
Sodium borohydride (830 mg) was added to a solution of (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (21.46 g) in tetrahydrofuran (500 ml) at 0° C. After the mixture was stirred at 0° C. for 4 hours, it was filtered, and the filtrate was diluted with ethyl acetate. Then the reaction was quenched by addition of a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the separated organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:2:1) as an eluent to afford the title compound (6.27 g, yield: 29%) as a pale yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:15][CH3:14])=[O:8]
Reactant: CN
Reactant: COc1ncc(Br)cc1C(=O)O
Agent: Cl
Product: CNC(=O)c1cc(Br)cnc1OC
Yield: 43 %

Procedure:
The title compound was synthesized as described for Intermediate example I-36 in 43% yield, starting from 5-bromo-2-methoxynicotinic acid and methylamine hydrochloride (4.3 equiv); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, 1 H), 8.26-8.35 (m, 1 H), 8.20 (d, 1 H), 3.95 (s, 3 H), 2.79 (d, 3 H); MS (APPI/APCI) m/z 245, 247[M+H+].
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22](=[O:24])[CH3:23])[C:14]=2[N:13]=1)C)(C)(C)C.[ClH:26]>CCOC(C)=O.O1CCOCC1>[ClH:26].[CH3:6][NH:7][CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22](=[O:24])[CH3:23])[C:14]=2[N:13]=1
Reactant: CC(=O)Nc1cccc2[nH]c(CCCN(C)C(=O)OC(C)(C)C)nc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNCCCc1nc2c(NC(C)=O)cccc2[nH]1

Procedure:
A solution of 1.84 g of [3-(4-Acetylamino-1H-benzoimidazol-2-yl)-propyl]-methyl-carbamic acid tert-butyl ester in 2.6 mL of EtOAc was treated with 7.75 mL of 4M-HCl in dioxane for 5 h and concentrated in vacuo to yield 1.7 g of N-[2-(3-methylamino-propyl)-1H-benzoimidazol-4-yl]-acetamide hydrochloride salt as yellow solid.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1.Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[N:25]1([CH2:24][CH2:23][S:1][C:2]2[S:6][C:5]([S:7][CH2:8][N:9]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[S:10]3(=[O:12])=[O:11])=[N:4][N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ClCCN1CCCCC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CSc1nnc(S)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2S(=O)(=O)N1CSc1nnc(SCCN2CCCCC2)s1
Yield: 60.2 %

Procedure:
Following a procedure similar to that described above in Example 33A, 0.69 g (0.002 mol) of 2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin was reacted with 0.74 g (0.004 mol) of 1-(2-chloroethyl)piperidine hydrochloride in 4 ml of DMF in the presence of 0.4 g of triethylamine to give 0.55 g (60%) of 2-(5-[2-(1-piperidinyl)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin, mp 100.0°-101.0° C. (from ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18]O)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2].[Cl:33]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O1CCCC1>[Cl:33][CH2:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)CN(c1cc(CO)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CN(c1cc(CCl)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1

Procedure:
The product of step (v) (0.5 g) in tetrahydrofuran (20 ml) was treated with triphosgene (0.114 g) then pyridine (0.183 g). After 16 hours the reaction was evaporated and purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 0.4 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]([N:8]([C:10]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=O)[CH3:9])=[O:7])[CH3:2].CNC1N=C(C(F)(F)F)C=CC=1C(OC)=O.C(C(C(Cl)=O)C(Cl)=O)C>ClCCCl>[OH:14][C:12]1[C:11]2[C:10](=[N:19][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:16]=2)[N:8]([CH3:9])[C:6](=[O:7])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:24]
Reactant: CCOC(=O)CC(=O)N(C)c1nc(C(F)(F)F)ccc1C(=O)OC
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: CNc1nc(C(F)(F)F)ccc1C(=O)OC
Solvent: ClCCCl
Product: CCOC(=O)c1c(O)c2ccc(C(F)(F)F)nc2n(C)c1=O
Temperature: 80 °C

Procedure:
Methyl 2-(3-ethoxy-N-methyl-3-oxopropanamido)-6-(trifluoromethyl)nicotinate. A mixture of methyl 2-(methylamino)-6-(trifluoromethyl)nicotinate (0.300 g) and ethyl malonoyl chloride (0.19 mL, 1.6 mmol) in 1,2-dichloroethane (50 mL) was heated to 80° C. for 63 hours. The reaction mixture was allowed to reach room temperature and was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (gradient: 0-30% EtOAc/hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 349 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)CC)C.O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N2CCC(O)C2)c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cccc(N2CCC(=O)C2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
A solution of 1-(3-cyanophenyl)-3-pyrrolidinol (0.65 g, 4.1 mmol) in triethyl amine (5.72 ml, 41 mmol) and DMSO (15 ml) was cooled to 0° C. and pyridine-SO3 (1.96 g, 12.3 mmol) was added. The mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hr. The reaction mixture was poured into water (100 ml) and extracted three times with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate and concentrated in vacuo to give 1-(3-cyanophenyl)-3-pyrrolidinone (0.41 g, 54%) that was used without purification.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[CH:4]=[C:5]([C:16]([O:18]CC)=[O:17])[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl>O1CCOCC1>[OH:1][C:2]1[C:3](=[O:21])[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[O:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(=O)c(O)c(-c2ccc(OC)cc2)o1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2oc(C(=O)O)cc(=O)c2O)cc1

Procedure:
A solution of ethyl 5-hydroxy-6-(4-methoxyphenyl)-4-oxo-4H-pyran-2-carboxylate (2.6 g), prepared as described in Example 47, in dioxan (30 ml) and concentrated hydrochloric acid (20 ml) was heated on a steam bath for 2 hours. The solid product was recrystallised from ethanol to give the title product (mp 258°-260° C. with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:13]([CH:9]1[CH2:8][C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1cccc2c1C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2cccc(OC)c2C1=O
Yield: 28 %

Procedure:
A solution of 26.4 g of 7-methoxy-1-indanone, 33.6 ml of 3-buten-2-ol and 265 mg of p-toluenesulfonic acid in 33.6 ml of 2,2-dimethoxypropane and 265 ml of anhydrous toluene was boiled under reflux for 17 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 9.9 g (28%) of (RS)-2-(2-buten-1-yl)-7-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)[C:25]([OH:27])=[O:26])(=O)=O)CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1C(=O)[C@H:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][N:56]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)=[CH:61][N:60]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[Cl:71][C:68]1[CH:69]=[CH:70][C:65]([C:62]2[CH:63]=[CH:64][C:59]([N:56]3[CH2:55][CH2:54][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:47])[CH3:48])[C:25]([OH:27])=[O:26])(=[O:51])=[O:52])[CH2:58][CH2:57]3)=[N:60][CH:61]=2)=[CH:66][CH:67]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Yield: 33 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-sulfonyl methyl}-3-methylbutyryl)-oxazolidin-2-one (0.312 g), to give the title compound as a white solid (0.077 g, 33%).
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[OH:13])([CH3:6])([CH3:5])[CH3:4].[CH3:33]I>C1COCC1>[C:3]([Si:7]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[O:13][CH3:33])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[Si](OCCCC(O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a suspension of NaH (153 mg 60% dispersed in mineral oil, 6.39 mmol) in 20 mL THF was slowly added at room temperature 4-(tert-butyl-diphenyl-silanyloxy)-1-(4-chloro-phenyl)-butan-1-ol (330 mg, 0.75 mmol) as a solution in 10 mL THF followed by the dropwise addition of methyl iodide (339 μL, 5.25 mmol). The reaction mixture was stirred for 3 h at room temperature before being quenched by the careful addition of saturated aqueous NH4Cl (30 mL). The mixture was extracted with ethylacetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL) and dried over sodium sulfate. After evaporation of solvent the product was isolated by flash column chromatography eluting with 0% to 30% ethyl acetate/hexane to give 343 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[S:22][C:23]([CH2:26]Cl)=[CH:24][CH:25]=1>>[Cl:20][C:21]1[S:22][C:23]([CH2:26][N:8]2[C:4]3[CH:3]=[C:2]([Cl:1])[C:18]([Cl:19])=[CH:17][C:5]=3[N:6]=[C:7]2[C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: ClCc1ccc(Cl)s1
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2Cc2ccc(Cl)s2)cc1

Procedure:
1-(5-Chlorothiophen-2-ylmethyl)-5,6-dichloro2-(4-formylphenyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and 2-chloro-5-chloromethylthiophene by following General Procedure 3.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[OH:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[N:1]1[C:15](=[O:16])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]1=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccccc2C[C@H]1O
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A suspension of (1R,2R)-1-aminoindan-2-ol (1.40 g, 0.00938 mol), phthalic anhydride (1.39 g, 0.00938 mol), and N,N-diisopropylethylamine (1.63 mL, 0.00935 mol) in toluene (141 mL) in a 250 mL round bottom flask equipped with a Dean-Stark trap and condenser was stirred at reflux under an atmosphere of nitrogen 18 h. The reaction mixture was cooled to rt. TLC showed complete conversion of starting material to a higher Rf spot. 1H NMR of an aliquot sample partitioned between EtOAc and water confirmed that reaction was complete. The reaction mixture was concentrated to a pale white and pale brown solid, redissolved in EtOAc (25 mL), washed with 1N HCl (2×10 mL), aqueous saturated NaHCO3 (1×10 mL), and brine (1×10 mL), dried over Na2SO4, filtered, concentrated, and dried on high vacuum to give the product as an off-white solid (2.53 g, 97%). 1H NMR (CDCl3, 400 MHz, δ): 7.86-7.84 (m, 2H), 7.74-7.72 (m, 2H), 7.26-7.25 (m, 2H), 7.20-7.14 (m, 1H), 7.01 (d, J=7.5 Hz, 1H), 5.67 (d, J=6.3 Hz, 1H), 5.14 (m, 1H), 3.58 (dd, J=7.5, 16.1 Hz, 1H), 2.97 (dd, J=6.8, 15.8 Hz, 1H), 2.12 (s, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7]2.[C:16]([O-])([O-:18])=[O:17].[K+].[K+].C(=O)=O>>[OH:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2ccc(C(F)(F)F)nc12
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc2ccc(C(F)(F)F)nc2c1O
Temperature: 170 °C
Yield: 48.4 %

Procedure:
8-Hydroxy-2-trifluoromethylquinoline (3.2 g) and K2CO3 (6.22 g) are placed in a stainless steel bomb. The bomb is pressurized slightly with CO2 and flushed 3×, then pressurized to approximately 800 psi CO2. The bomb is heated to 170° C., reaching a final pressure of approximately 1200 psi. This temperature and pressure are maintained for 7 days after which time the bomb is cooled and the pressure released. The solid residue is dissolved in a minimal amount of warm water. Any undissolved material is filtered and the aqueous filtrate is acidified to pH 4 with conc. HCl. The resulting tan solid is filtered and dried. The product is recrystallized with Et2O to give a light tan solid (1.87 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:32])[C:10]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[C:24]([C:25]([OH:27])=O)=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[N:21]2)[CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:67][O:68][C:69]1[CH:76]=[CH:75][CH:74]=[CH:73][C:70]=1[CH2:71][NH2:72]>C(Cl)Cl>[CH3:67][O:68][C:69]1[CH:76]=[CH:75][CH:74]=[CH:73][C:70]=1[CH2:71][NH:72][C:25]([C:24]1[N:20]([C:18]2[N:19]=[C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH3:32])[CH:15]=[CH:16][CH:17]=2)[N:21]=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=1)=[O:27]
Reactant: COc1ccccc1CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(-n2nc(C(F)(F)F)cc2C(=O)O)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 21 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a stirred solution of 49 (38 mg, 0.083 mmol) in CH2Cl2 (0.83 mL) were added triethylamine (0.025 mL, 0.183 mmol) and BOP (44.1 mg, 0.100 mmol) followed by 2-methoxybenzylamine (0.013 mL, 0.100 mmol). The resulting solution was allowed to stir at 21° C. overnight and evaporated to dryness. The residue was purified via ISCO flash chromatography (40% to 100% EtOAc/hexanes; 12G column). The title product 50 (28 mg, 59% yield) was isolated as a pale yellow oil. LRMS (ESI): calc. 576.6; found 577.6 (MH)+.
Reaction SMILES: [Br:1]Br.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[CH3:4]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:3][CH3:4])=[CH:7][C:8]=1[F:12]
Reactant: BrBr
Reactant: CCSc1cccc(F)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCSc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Bromine (0.3 ml) was added to a solution of 1-ethylsulfanyl-3-fluoro-benzene (1 g) in chloroform (20 ml) at 0° C. then warmed to RT. After 2 h the mixture was diluted with DCM, washed with aq. sodium thiosulphate solution, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% diethylether/iso-hexane. Yield 1.2 g
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)[CH2:30]C>>[CH2:29]([O:32][C:33](=[O:43])[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:39][CH:40]=1)[CH3:30]
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCCOC(=O)Cc1ccc(CBr)cc1
Product: CCOC(=O)Cc1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (4-Bromomethyl-phenyl)-acetic acid propyl ester as in the procedure of Example 43. MS (ESI) m/z 556;
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:9]=[C:4]2[CH:3]=[N:2]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[C:5]3=[CH:6][N:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:9]=[C:4]3[CH:3]=[N:2]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2cn[nH]c2cn1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2cnn(Cc3ccc(F)cc3)c2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a stirring solution of methyl 1H-pyrazolo[3,4-c]pyridine-5-carboxylate (0.628 g, 3.545 mmol) in DMF (15 mL) was added 4-fluorobenzyl bromide (0.442 mL, 3.545 mmol) followed by potassium carbonate (0.490 g, 3.545 mmol), and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude solid was purified by flash column chromatography (silica gel, 0-20% acetonitrile:chloroform v/v) to provide pure desired methyl 1-(4-fluorobenzyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate (0.66 g, 30% yield over three steps) and the undesired methyl 2-(4-fluoro-benzyl)-2H-pyrazolo[3,4-c]pyridine-5-carboxylate (0.73 g, 33% yield) as white solids. Methyl 1-(4-fluorobenzyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate: 1HNMR (CDCl3, 300 MHz) δ ppm 8.91 (s, 1H), 8.59 (s, 1H), 8.22 (s, 1H), 7.26 (m, 2H), 7.02 (m, 2H), 5.69 (s, 2H), 4.03 (s, 3H). LCMS (API-ES M+H+) 286. Methyl 2-(4-fluoro-benzyl)-2H-pyrazolo[3,4-c]pyridine-5-carboxylate: 1HNMR (CDCl3, 300 MHz): 6 ppm 9.32 (s, 1H), 8.51 (s, 1H), 8.10 (s, 1H), 7.36 (m, 2H), 7.09 (m, 2H), 5.65 (2H, s), 4.02 (s, 3H). LCMS (API-ES M+H+) 286.