Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.B.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[CH2:26]([C:28]1[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][C:31]2[N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:30]=2[CH:29]=1)[CH3:27].CO>ClCCl>[C:41]([O:40][C:38]([N:32]1[CH2:33][CH2:34][CH2:35][C@@H:36]([OH:37])[C:30]2[CH:29]=[C:28]([CH2:26][CH3:27])[C:46]([C:47]([F:50])([F:48])[F:49])=[CH:45][C:31]1=2)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCCC2=O
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@H]2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Add a solution of borane dimethylsulfide complex (16.0 mL, 16.0 mmol, 1M in tetrahydrofuran) dropwise to a solution of (S)-2-methyl-CBS-oxazaborolidine (7.50 mL, 7.50 mmol, 1M in toluene) in dichloromethane (100 mL) at −30° C. under nitrogen. Stir the mixture for 30 min and add a solution of tert-butyl 7-ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (8.60 g, 24.0 mmol) in dichloromethane (50 mL) dropwise and warm the mixture slowly to 0° C. over a period of 6 h. Pour the mixture into methanol (200 mL) at −20° C. and slowly warm the stirring mixture to room temperature over 1 h. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a colorless oil (7.62 g, 88%): TLC Rf 0.49 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.21-2.30 (m, 19H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 1H), 7.31-7.45 (m, 2H); Chiral HPLC (OD Column) 91.6% ee; APCI MS m/z 360 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.ClS([N:19]=[C:20]=O)(=O)=O.CN(C)C=O.O>C(COC)OC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:19])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(C#N)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A sample of 2-p-chlorophenyl-3-cyanopyrrole, prepared by the method of Example 4, (3.0 g, 0.015 mole) is dissolved in 50 mL of dry dimethoxyethane. To this solution is added chlorosulfonyl isocyanate (3.39 g, 0.024 mole). The addition is exothermic and some cooling is necessary. After stirring 3 hours at room temperature, dimethylformamide (6-7 mL) is added and the solution is stirred 4 hours more. The solution is then poured into water precipitating a white solid (3.4 g, 100%). A sample (1.0 g) is purified by dissolving in ethyl acetate and then passing the solution through a 60 mL course filter funnel packed with silica gel. The filtrate is concentrated to yield 0.7 g of a white solid with mp 235°-240° C.
Reaction SMILES: [C:1]([O:9]C)(=[O:8])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C.Cl>>[CH3:7][O:6][C:4](=[O:5])[C:3](=[CH:23][CH:20]1[CH2:19][CH2:18][CH:17]([O:16][Si:15]([C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:26])[CH3:25])[CH2:22][CH2:21]1)[CH2:2][C:1]([OH:9])=[O:8]
Reactant: COC(=O)CCC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)CC(=O)O
Temperature: 50 °C
Yield: 38.3 %

Procedure:
A solution of dimethyl succinate (730 mg, 5.0 mmol) and 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanecarbaldehyde (1.00 g, 4.1 mmol) was added over 25 min to a 1.0M solution of potassium tert-butoxide in tert-butanol (4.4 mL. 4.4 mmol). The reaction mixture was heated at 50° C. for 50 min, cooled to RT and concentrated under vacuum. The residue was dissolved in water (25 mL) and washed with EtOAc (2×10 mL). The aqueous layer was acidified with 6 N HCl (2.0 mL, 12 mmol) and extracted with EtOAc (2×20 mL), dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (25% EtOAc/DCM) to give the title compound (560 mg) as a mixture of olefin isomers (˜1:1) and a mixture of cis and trans isomers at the cyclohexyl ring (−1:1). 1H NMR (CDCl3, 400 mHz) δ (ppm) olefin peaks at 6.88 (d, J=10.2 Hz) 6.77 (d, J=10.0 Hz) CHOTBS peaks at 3.96 ppm (br s) (cis isomer, hydrogen equitorial, 3.55 (m) (trans isomer, hydrogen axial).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2.C(O)(=O)C(C(C(O)=O)O)[OH:37]>CCCCCC.CCOCC>[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:37])=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cc3)ccc21
Reaction time: 0.67 h
Yield: 38 %

Procedure:
56 ml (67 millimoles) of a 20% strength solution of diisobutylaluminum hydride in hexane were added to a solution of 10 g (32 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1) in 120 ml of absolute ether. The mixture was stirred for a further 40 minutes, 150 ml of saturated tartaric acid solution were added dropwise and stirring was continued for a further hour. Thereafter, the mixture was extracted three times with ether and the combined ether phases were washed twice with water, dried over Na2SO4 and evaporated down. Recrystallization of the residue from isopropanol gave 3.6 g (38%) of the title compound of melting point 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:56][CH2:57][CH2:58][N:59]1[CH2:63][CH2:62][CH:61]([NH:64][C:65](=[O:67])[CH3:66])[CH2:60]1>CN(C=O)C>[C:65]([NH:64][CH:61]1[CH2:62][CH2:63][N:59]([CH2:58][CH2:57][NH:56][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:60]1)(=[O:67])[CH3:66]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CC(=O)NC1CCN(CCN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(CCNC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)C1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (252 mg, 0.5 mmol) in DMF (10 mL) was added HOBt (101 mg, 1.5 eq.), EDAC.HCl (144 mg, 1.5 eq.) and TEA (152 mg, 3 eq.). After stirring at rf for 30 mins, to the mixture was added N-[1-(2-amino-ethyl)-pyrrolidin-3-yl]-acetamide (128 mg, 1.5 eq.). After stirring at 30° C. for 72 hours, the reaction was concentrated and the residue was purified on a silica gel column to give 213 mg (65%) of the titled compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1)[N:5]([C:8](=[CH:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=O.C([O-])(=O)C1C=CC=CC=1.[NH4+:31].C1(C)C(C)=CC=CC=1.O>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([N:5]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:31]=[CH:6]2)[C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C(=CO)N(C=O)c1c(CC)ccc(Cl)c1C
Agent: O=C([O-])c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cncn1-c1c(CC)ccc(Cl)c1C
Yield: 76.4 %

Procedure:
19.2 g (0.068 mol) of ethyl 2-(3-chloro-6-ethyl-2-methyl-N-formylanilino)-3-hydroxy-acrylate were heated to an internal temperature of 153° C. with 12.3 g (0.088 mol) of ammonium benzoate in 100 ml of xylene with removal of the xylene/water mixture by distillation. The mixture was allowed to cool and was taken up in toluene, and the organic phase was washed twice with 2N sodium hydroxide solution and twice with water, dried over sodium sulfate and evaporated. 15.2 g (85% of theory) of ethyl 1-(3-chloro-6-ethyl-2-methylphenyl)-imidazole-5-carboxylate were obtained as a pale brown oil. Identification was effected by 1H NMR spectroscopy.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]([O:8][C:9]1[C:10]([Cl:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])(=[O:7])[CH3:6].[C-]#N.[Na+].O>CN(C)C=O>[C:5]([O:8][C:9]1[C:10]([Cl:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]([CH2:3][CH2:2][C:1]#[N:4])=[O:13])(=[O:7])[CH3:6]
Reactant: C=CC#N
Reactant: CC(=O)Oc1cccc(C=O)c1Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(=O)CCC#N)c1Cl
Temperature: 35 °C
Reaction time: 4 h

Procedure:
A solution of redistilled acrylonitrile (20 g, 0.375 mole) in dimethylformamide (100 ml) was added dropwise to a stirred solution of 3-acetoxy-2-chlorobenzaldehyde (99.2 g, 0.5 mole) and sodium cyanide (12.25 g, 0.25 mole) in dimethylformamide (250 ml) at 35° C during 30 minutes. The mixture was stirred at 35° C for 4 hours, then poured into twice its own volume of water and the mixture was extracted with chloroform. The washed and dried extract was evaporated to give 3-(3-acetoxy-2-chlorobenzoyl)propionitrile.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N([O-])=[O:12].[Na+].[OH-].[Na+]>O.OS(O)(=O)=O>[S:8]1[C:4]2[CH:3]=[C:2]([OH:12])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2ncsc2c1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-aminobenzothiazole (1.0 g, 6.66 mmol) in water (22 mL) and H2SO4 (16 mL) at 5° C. was added a solution of sodium nitrite (460 mg, 6.72 mmol) in water (13 mL) keeping the temperature below 5° C. The resulting solution was allowed to stir for 15 minutes. The reaction mixture was heated to 160° C. and a solution of H2SO4 (50 mL) and water (38 mL) was slowly added. The resulting mixture was allowed to stir for 1 h. The mixture was allowed to cool and an aqueous solution of 50% sodium hydroxide was added until the pH=7. The mixture was extracted with ethyl acetate and washed with brine. The combined organic was dried over MgSO4 and evaporated to yield a semi-solid. The semi-solid was purified by column chromatography (40% ethyl acetate/hexanes) to yield benzothiazo-6-ol 16 as an off-white solid. Synthesis of 6-(oxiran-2-ylmethoxy)benzothiazole (48):
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:42][CH:43]([CH3:52])[C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>ClCCl>[C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:6]([C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=2)[CH:1]=[O:2])=[O:8])[CH2:48][CH2:47]1)(=[O:45])[CH:43]([CH3:52])[CH3:42]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(C)C(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol), 1-hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (1.05 g, 5.5 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and 2-methyl-1-(piperazin-1-yl)propan-1-one hydrochloride (1.06 g, 5.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (50 mL×2), 10% citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (1.44 g, yield 95%) as a gum. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.13-1.14 (d, J=6.8 Hz, 6H), 2.80 (s, 1H), 3.46-3.80 (m, 8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.69-7.71 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.96-7.99 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 10.06 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([O:29][CH3:30])[C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[C:27]([O:29][CH3:30])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: COc1nc(Cl)ccc1C(C)(C)O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: COc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.19 mmol) and 2-(6-chloro-2-methoxypyridin-3-yl)propan-2-ol (39 mg, 0.19 mmol) as starting materials.
Reaction SMILES: [CH2:1]([C:8]1[C:31](=[O:32])[N:11]2[CH:12]=[C:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:14][C:15]([S:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[C:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl.CN(C)C1C=CN=CC=1>[C:33]([O:32][C:31]1[N:11]2[CH:12]=[C:13]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:14]=[C:15]([S:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]2=[N:9][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1ccc(Sc2[nH]c(-c3ccccc3)cn3c(=O)c(Cc4ccccc4)nc2-3)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Sc2nc(-c3ccccc3)cn3c(OC(C)=O)c(Cc4ccccc4)nc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of 231 (25 mg, 0.06 mmol) in 4 mL of dichloromethane, acetyl chloride (8 μL, 0.12 mmol) and 4-(dimethylamino)pyridine (DMAP) (5 mg, 0.03 mmol) were added, the resulting mixture was stirred at room temperature for 15 min. Then the solution was washed with water and the organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure to obtain 18 mg (yield 66%) of 25a as a red oil. 1H-NMR (CDCl3): 2.10 (s, 3H), 3.88 (s, 3H), 4.20 (s, 2H), 7.00-7.02 (m, 2H), 7.22-7.33 (m, 8H), 7.61-7.64 (m, 4H), 7.68 (s, 1H). MS (ESI): m/z 482 (M+H+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[C@@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(=O)N[C@@H]1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)—N-(pyrrolidin-3-yl)acetamide. MS (m/e): 428.3 (MH+).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[C:42]([O:48][CH3:49])[CH:41]=1>CC#N>[NH2:45][CH2:44][C:43]1[CH:46]=[CH:47][C:40]([CH2:39][N:18]([CH2:17][C:9]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:41][C:42]=1[O:48][CH3:49]
Reactant: COc1cc(CBr)ccc1C#N
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)ccc1CN
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.386 g, 1.02 mmol) in CH3CN (10 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.00 mmol) followed by of 4-(bromomethyl)-2-methoxybenzonitrile (0.363 g, 1.60 mmol). The resultant mixture was heated to 60° C. for 15 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (40 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) followed by radial chromatography on silica gel (2 mm plate, 2:1 hexanes-EtOAc) provided 0.30 g (56%) of a white foam.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[N:16]=[C:15]([O:33][CH3:34])[N:14]=2)[CH:10]=[CH:9][C:8]=1[F:35])([CH3:6])[CH3:5].[OH-].[Na+]>O.CO.C1COCC1>[F:35][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)[N:16]=[C:15]([O:33][CH3:34])[N:14]=2)=[CH:12][C:7]=1[C:4]([CH3:6])([CH3:5])[C:3]([OH:36])=[O:2]
Reactant: COC(=O)C(C)(C)c1cc(-c2cc(NCCc3ccc(OC(F)(F)F)cc3)nc(OC)n2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2ccc(F)c(C(C)(C)C(=O)O)c2)n1

Procedure:
A mixture of 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (should this be the right starting material? 1.9 g) and sodium hydroxide (2.46 g) in water (19 mL), MeOH (19 mL) and THF (19 mL) is stirred at 40° C. for 40 hours. The solution is evaporated in vacuo and acidified to pH=6 with concentrated HCl (1.6 mL). The solid is filtered, air dried and chromatographed on silica gel eluting with 50% EtOAc in heptane to afford 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (1.12 g, Example 70). MS: 494 (M+H); 1H NMR (300 MHz, CD3OD) 07.8, (d, 1H, J=0.3 Hz); 7.7 (m, 1H); 7.4 (d, 2H, J=0.4 Hz); 7.2-7.3 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 3.9 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H). IC50=193 mM
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:31])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 17.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2-methyl-phenylboronic acid (27 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (9 mg, 18%). LC-MS m/e 401.29 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:14][OH:15])[CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1.[CH3:20][C:21]1[CH:26]=[C:25](O)[CH:24]=[C:23]([CH3:28])[C:22]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:14][O:15][C:25]2[CH:26]=[C:21]([CH3:20])[C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[C:23]([CH3:28])[CH:24]=2)[CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1
Reactant: C=CCC(CO)(CC=C)c1ccc(C(=O)OC)cc1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A solution of 4-(1-allyl-1-hydroxymethyl-but-3-enyl)-benzoic acid methyl ester (0.768 g, 2.95 mmol), 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol (0.861 g, 3.23 mmol), and triphenylphosphine (1.180 g, 4.50 mmol) in toluene (30 mL) is treated with 1,1′-(azodicarbonyl)-dipiperidine (1.182 g, 4.68 mmol) and stirred overnight at 80° C. The reaction mixture is then cooled to room temperature, diluted with MeOH, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% EtOAc to 40% EtOAc to provide 0.964 g (64%) of the title compound as a clear syrup. 1H NMR (CDCl3): δ 8.02-8.00 (m, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.46-7.44 (m, 2H), 7.26 (d, J=7.8 Hz, 2H), 6.68 (s, 2H), 5.60-5.54 (m, 2H), 5.08-5.00 (m, 4H), 4.15 (s, 2H), 3.91 (s, 3H), 2.66 (d, J=7.6 Hz, 4H), 1.99 (s, 6H).