Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3]
Reactant: COc1cc(C(C)(C)O)c(O)cc1N1CCNCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a stirred suspension of 2-(1-Hydroxy-1-methyl-ethyl)4-methoxy-5-piperazin-1-yl-phenol (0.5 g, 1.9 mmol) in dichloromethane under nitrogen at room temperature was aded trifluoroacetic acid (7.2 mL, 93.86 mmol) followed by triethyl silane (3.0 mL, 18.8 mmol). The reaction mixture was stirred for 18 hours at room temperature, and then was evaporated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure to afford 0.47 g (99% ) of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[CH2:27][CH2:26][N:25]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNCC4)no2)cc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CC(=O)OC(C)(C)C)CC4)no2)cc1Cl
Temperature: 100 °C
Yield: 92 %

Procedure:
In a 5 ml microwave reaction vessel was added 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 8) (110 mg, 0.262 mmol). Then potassium carbonate (101 mg) was added followed by 1,1-dimethylethyl bromoacetate (51.0 mg, 0.262 mmol). The reaction mixture was heated at 100° C. for 10 minutes. The cooled reaction mixture was diluted with DCM (5 ml) and purified by SCX (washing with methanol and eluting the crude amino ester with methanolic ammonia). 1,1-dimethylethyl [6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]acetate (120 mg, 0.241 mmol, 92% yield) was isolated as a pale yellow oil. MS (ES) C27H3235ClN3O4 requires 497; found 498 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12]>C(O)(=O)C.C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([Cl:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(Cl)ccc(N)c1Cl
Yield: 96 %

Procedure:
To a solution of 2,6-dichloro-3-nitrotoluene (50 g) in acetic acid (400 ml) and ethanol (200 ml) was added iron (67.8 g) and the mixture was refluxed for 1.5 hours under nitrogen atmosphere. The insoluble material was filtered off and the filtrate was concentrated. To the residue was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate three times and brine, dried over magnesium sulfate, and concentrated in vacuo to give 2,4-dichloro-3-methylaniline (41 g).
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[O:10])[NH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.[H-].[Na+]>CN(C=O)C>[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:4]1[C:2](=[O:3])[CH:1]([NH:8][C:9]([NH2:11])=[O:10])[NH:7][C:5]1=[O:6]
Reactant: BrCc1cccc(I)c1
Reactant: NC(=O)NC1NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)NC1NC(=O)N(Cc2cccc(I)c2)C1=O
Yield: 13.6 %

Procedure:
Allantoin (1.58 g) was stirred with meta-iodobenzyl bromide (2.97 g) in DMF (25 ml) at 21° under nitrogen and sodium hydride (60% oil dispersion; 0.40 g) was added over 5 min. After 2 h the solution was partitioned between EtOAc and water and hydrochloric acid was added to give pH 3. The separated aqueous layer was extracted with more EtOAc and the combined organic layers were washed with water and brine twice. After drying (MgSO4), the solution was concentrated to 20 ml. After 1 h the solid was collected by filtration and washed with EtOAc. The residue was boiled with EtOAc (50 ml) and the slurry was allowed to cool. The solid was collected by filtration, washed with ethyl acetate and dried to give the title compound (0.507 g). LCMS RT=2.44 min
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[Cl:1][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])[CH:22]=2)[N:18]([S:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:16])=[O:17])[CH:19]=1
Reactant: CC(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccc2c(c1)c(Cl)cn2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 108.7 %

Procedure:
N-chlorosuccinimide (0.42 g, 3.2 mmol) was added to a solution of N-(2-{[1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 25, 0.95 g, 2.6 mmol) in THF (20 ml) at room temperature. The reaction mixture was stirred at 40° C. for 6 hours. The reaction mixture was evaporated and the crude material was purified by flash chromatography on silica gel using 3% MeOH in DCM as the eluent to give the title compound (1.11 g) as a white solid. MS m/z 393 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][C:24](N=[N+]=[N-])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CC(C)=O>[C:19]([O:23][C:24]([NH:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: NCc1ccsc1CC(=O)O
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccsc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 3-aminomethyl-2-thienylacetic acid 8 (3.1 g, 18 m. moles) and triethylamine (8 g. 80 m moles) in 50% aqueous acetone (80 ml) was added dropwise t-butoxycarbonyl azide (5.7 g, 40 m moles) over a period of 20 mins. at 0° C. with vigorous stirring. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The concentrate was washed with ether (2×20 ml), adjusted to pH 2 with conc. HCl and extracted with ethyl acetate (2×50 ml). The ethyl acetate extracts were washed with saturated aqueous sodium chloride, dried over MgSO4, treated with charcoal and evaporated under reduced pressure. The residue was triturated with n-hexane and crystallized from n-hexane and benzene to give 4.5 g (92%) of colorless needles 9, melting at 62°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:32]([N:40]1[CH2:45][CH2:44][N:43]([C:22]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)=[CH:26][CH:25]=2)=[O:24])[CH2:42][CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccccc1)N1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-benzoylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=619.98 (M+H+); retention time=0.82 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](Cl)=[N:24][N:23]=1>CC(O)(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:22]([Cl:21])=[N:23][N:24]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: CC(C)(C)O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1

Procedure:
In a 150 mL pressure tube was dissolved 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (6.1 g, 23 mmol) in tBuOH (75 mL). To this solution was added 1,4-dichlorophthalazine (10.0 g, 50 mmol) and the mixture was placed in pre-heated oil bath at 100° C. A thick clay formed at the bottom of the tube after 20 minutes. LCMS on solid at the bottom of the tube showed mainly desired product with trace amounts of starting material. This solid material was dissolved and transferred to a flask using hot 90/10/1 (CH2Cl2/MeOH/ammonium hydroxide), and evaporated to dryness. The crude was dissolved in CH2Cl2 and washed with sat. sodium bicarbonate. The organic layer was separated and dried over sodium sulfate, and then concentrated. The mixture was then dissolved in approx. 30/70 MeOH/CH2Cl2, silica was added and the mix was concentrated to dryness. This silica pre-absorbed material was purified using 0 to 100% 90/10/1 (CH2Cl2/MeOH/ammonium hydroxide) to afford the title compound. MS Found: [M+H]=430.0. Calc'd for C23H16ClN5O2: 429.9.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1>C1COCC1>[CH2:17]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: OCCCCCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,6-hexan-diol in dry THF at 0° C., NaH (1.1 equiv) was added. After stirring for 30 min, BnBr (1 equiv) was added slowly dropwise using a syringe and stirred for additional 3 h. After completion of the reaction (monitored by TLC), it was quenched with ice and the organic layer was extracted using ether and washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuum and concentrated. The crude was purified by chromatographic technique (EtOAc:pet ether=20:80). 1H NMR (CDCl3, 200 MHz) δ 7.3-7.4 (5H, m), 4.5 (s, 2H), 3.6 (t, 2H), 3.4 (t, 2H), 1.8 (br s, 1H), 1.6 (m, 4H), 1.4 (m, 4H); 13C NMR (CDCl3, 50 MHz): 138.56, 128.34, 127.62, 127.50, 72.87, 70.29, 62.63, 32.67, 29.73, 26.03, 25.62
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([N:33]=[C:34]=[S:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:25]([NH:33][C:34]([NH:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[S:16][C:17]=2[CH:23]=1)=[S:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccc2nc(NC3CCN(Cc4ccccc4)CC3)sc2c1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ccc2nc(NC3CCN(Cc4ccccc4)CC3)sc2c1)c1ccccc1
Yield: 100 %

Procedure:
N2-(1-Benzyl-piperidin-4-yl)-benzothiazole-2,6-diamine (Example 27b, 39 mg, 0.12 mmol) was stirred with benzoylisothiocyanate (17 μl, 1.1 eq.) in dry THF at room temperature under argon for 24 hours. The solvent was evaporated to give a yellow oil. The oil was purified by chromatography on silica gel (30% ethyl acetate/hexanes) to give a yellow oil (60.7 mg, 100%).
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[CH2:15](C1CCC(C2CCC(=O)CC2)CC1)C>>[CH2:5]([CH:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]1)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:15]
Reactant: CCC1CCC(C2CCC(=O)CC2)CC1
Reactant: CC1CCC(C2CCC(=O)CC2)CC1
Product: CCCCCCCC1CCC(=O)CC1

Procedure:
4-(4-methylcyclohexyl)cyclohexanone [151772-66-6]; 4-(4-ethylcyclohexyl)cyclohexanone [150763-46-5];
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)=[O:4].[Br:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:13][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:11])[Cl:12])[N:6]([CH3:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1cc(Br)cc1C(=O)C(Cl)(Cl)Cl
Yield: 68.7 %

Procedure:
Under an ice cooling, N-methylpyrrole (8.10 g, 100 mmol) was dissolved in methylene chloride (100 ml), and trichloroacetyl chloride (20.00 g, 115 mmol) was added thereto. Thereafter, the mixture was stirred at a room temperature for 16 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. Thus, 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (16.3 g, 72%) was obtained. The resulting 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (15.0 g, 66.7 mmol) was dissolved in chloroform (150 ml), and N-bromosuccinimide (12.5 g, 70.2 mmol) was added thereto at a room temperature. The mixture was heated under reflux for 16 hours. After the mixture was allowed to cool, a saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give the title compound (14.0 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:16]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([S:22]([CH2:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)(=[O:24])=[O:23])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2cccnc2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)Cc2cccnc2)cc1

Procedure:
1 g of 3-(bromomethyl)pyridine hydrobromide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(pyridin-3-ylmethylthio)benzoate. 980 mg of methyl 4-(pyridin-3-ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate. 760 mg of methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-3-ylmethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-3-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11]O)[CH:3]=1.O=S(Cl)[Cl:15]>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][Cl:15])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)c2c(c1)OCO2
Solvent: ClCCl
Product: ClCc1cc(Cl)c2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol (5.5 g, 30 mmol) and SOCl2 (5.0 mL, 67 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1 h and was then poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL×3). The combined extracts were washed with water and aqueous NaHCO3 solution, dried over Na2SO4 and evaporated under reduced pressure to afford 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole, which was directly used in the next step.
Reaction SMILES: Cl[C:2]1[C:13]2[NH:12][N:11]=[N:10][C:9]=2[C:8]2[CH2:7][C:6]34[CH2:24][CH:16]([C:17](=[O:23])[C:18]([C:19]([F:22])([F:21])[F:20])=[C:5]3[C:4]=2[CH:3]=1)[CH2:15][CH2:14]4>CN(C=O)C.ClCCl.[OH-].[OH-].[Pd+2].[Pd]>[F:21][C:19]([F:20])([F:22])[C:18]1[C:17](=[O:23])[CH:16]2[CH2:24][C:6]3([CH2:7][C:8]4[C:9]5[N:10]=[N:11][NH:12][C:13]=5[CH:2]=[CH:3][C:4]=4[C:5]=13)[CH2:14][CH2:15]2
Reactant: O=C1C(C(F)(F)F)=C2c3cc(Cl)c4[nH]nnc4c3CC23CCC1C3
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3CC23CCC1C3
Reaction time: 29 h

Procedure:
To a solution of 4-chloro-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one (2.3 g, crude product from the preceding step, ˜6.1 mmol) in DMF (230 mL) were added 20% Pd(OH)2 on carbon (1 g) and 5% palladium on calcium carbonate (1 g) and the mixture was hydrogenated at atmospheric pressure. After 29 hours, additional 20% Pd(OH)2 on carbon (175 mg) and 5% palladium on calcium carbonate (175 mg) were added. After 24 hours more, the mixture was filtered through a pad of Celite®, washing thoroughly with EtOAc. The filtrate was partitioned between EtOAc and water which had been acidified with a small amount of 1N hydrochloric acid. The aqueous layer was thoroughly extracted with EtOAc and the combined organic layers were washed with 1N hydrochloric acid, water and brine. After drying over MgSO4, the solvent was removed under reduced pressure to give an oily solid which was dissolved in dichloromethane and evaporated to give a solid. Chromatography on silica gel (elution with 1:1 EtOAc/hexanes+0.1% HOAc followed by 99:99:2 EtOAc/hexanes/methanol+0.1% HOAc) gave 6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([CH3:33])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]=1[CH3:33]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: Cc1c(F)cccc1B(O)O
Product: Cc1c(F)cccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 7 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-fluoro-2-methylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2,3′-difluoro-2′-methylbiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 7%): m/z (ES+) 397 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(NS(C)(=O)=O)cc3)c2CC1
Reaction time: 0.08 h

Procedure:
To a solution of 0.022 g of 1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 99) in DMF (1 mL) was added 1 equivalent of triethylamine. After 5 min, 1 equivalent of methanesulfonyl chloride was added and the mixture was stirred overnight. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The resulting oil was purified by preparative TLC (50% EtOAc/hexanes) to give 1-(4-methanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. This mono-mesylate was then dissolved in 9:1 CH2Cl2/MeOH (2 mL) and treated with 3 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The resulting oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.004 g of the title compound as a white solid. MS (ESI): exact mass calculated for C21H24N4O2S, 396.16. found, m/z 397.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.42 (t, J=7.7 Hz, 2H), 7.37-7.34 (m, 1H), 7.22-7.20 (m, 2H), 7.13-7.10 (m, 2H), 5.34 (s, 2H), 2.97-2.93 (m, 4H), 2.92 (s, 3H), 2.90-2.87 (m, 2H), 2.82-2.78 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([O:16]CC2C=CC=CC=2)=[O:15])=[O:8])=[CH:3][CH:2]=1.[H][H]>C1COCC1.C(O)C.[Pd]>[N:1]1[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([OH:16])=[O:15])=[O:8])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1CCCN1C(=O)c1ccncc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCCN1C(=O)c1ccncc1

Procedure:
Benzyl 1-(pyridine-4-carbonyl)pyrrolidine-2-carboxylate (4.0 g, 11.5 mmol) is dissolved at RT in a mixture of THF and ethanol abs. (1:1, 30 ml), and treated with palladium on active carbon (10%, 0.7 g). Evacuation is then carried out three times and the vacuum is replaced by hydrogen from a balloon.
Reaction SMILES: [F:1][C:2]([F:16])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[CH2:17]([S:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:18][CH3:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:17]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:16])[F:1])=[CH:28][CH:29]=1)(=[O:22])=[O:21])[CH2:18][CH3:19]
Reactant: O=C(Cl)CCCCCCCCCC=C(F)F
Reactant: CCCS(=O)(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)c1ccc(NC(=O)CCCCCCCCCC=C(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8.5 g of 12,12-difluorododec-11-enoic acid chloride are added at room temperature to 3.45 g of 4-propylsulfonylaniline, 2.5 g of triethylamine and 100 mg of 4-dimethylaminopyridine in 50 ml of toluene and the mixture is stirred for 2 days at room temperature. A further 50 ml of toluene is then added, the toluene phase is washed with water, dried over sodium sulfate and concentrated to dryness by evaporation in vacuo. The residue is chromatographed on silica gel with hexane:ethyl acetate (7:3), yielding the title compound having a melting point of 67°-70° C. (compound no. 3-4).