Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH:28]([CH3:30])[CH3:29])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].C1C(=O)N([Cl:38])C(=O)C1>C(Cl)Cl>[Cl:38][C:11]1[C:10]2[CH:9]=[C:8]([O:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([O:27][CH:28]([CH3:30])[CH3:29])=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:16]=[CH:15][C:14]=2[N:13]2[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=12
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C#N
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CCC2CC(=O)O)cc1C#N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the enantiomer obtained during the resolution of Compound 6 by chiral HPLC (described as the enantiomer isolated and having the retention time of 6.7 min per the conditions reported in Example 1.2) (20 mg, 0.049 mmol) in DCM. (0.500 mL) was cooled to 0° C. NCS (6.60 mg, 0.049 mmol) was added and the reaction was allowed to continue at 0° C. for 15 min in a 20 mL sealed scintillation vial. After 15 min, the reaction mixture was diluted with DCM and washed with water (2×10 mL), then washed with sodium thiosulfate pentahydrate (aq) (2×10 mL), dried over MgSO4 and filtered by vacuum filtration. The filtrate was concentrated under reduced pressure to give an enantiomer of Compound 8 as a yellow solid (16.7 mg). LCMS m/z=439.8 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=5.94 Hz, 6H), 2.25-2.34 (m, 1H), 2.52-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.29, 4.17 Hz, 1H), 3.63-3.73 (m, 1H), 3.96-4.04 (m, 1H), 4.12-4.19 (m, 1H), 4.76-4.83 (m, 1H), 5.07 (s, 2H), 6.86 (dd, J=8.84, 2.40 Hz, 1H), 6.96 (d, J=2.40 Hz, 1H), 7.28 (d, J=3.66 Hz, 1H), 7.30 (d, J=3.66 Hz, 1H), 7.72 (dd, J=8.72, 2.27 Hz, 1H), 7.79 (d, J=2.15 Hz, 1H), 12.32 (bs, 1H).
Reaction SMILES: [Br:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:7][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCc1ccc(C(Br)COc2ccc(C=C3SC(=O)NC3=O)cc2)nc1

Procedure:
To stirred solution of 5 g (0.015 mol) 4-[2-bromo-2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde dissolved in 50 ml, toluene was added 1.85 g (0.015 mol) thiazolidin-2,4-dione followed by addition of 2 g (0.03 mol) acetic acid and 3 g (0.03 mol) piperidine. Reaction mixture was heated and water was removed azeotropically. After completion of the reaction on TLC, toluene was distilled out completely under reduced pressure. Product was poured into excess of water and extracted with ethyl acetate. On concentrating ethyl acetate in vacuo, 0.65 g (10%) desired product obtained with satisfactory mass. The 1H NMR was similar to the 1H NMR of example 79.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)Br.[N+](C1OC(C=O)=CC=1)([O-])=[O:26]>C(Cl)Cl.[Zn]>[C:14]1([P:7](=[O:26])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrC(Br)(Br)Br
Agent: [Zn]
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6.5 g of zinc dust in 300 ml of methylene chloride was added, successively, 26.2 g of triphenylphosphine and 33.2 g of carbon tetrabromide. A mildly exothermic reaction carried the temperature of the mixture to 35°-40°, no cooling being applied. The mixture then was stirred for one hour at room temperature, then cooled to 15° and treated with 10.7 g of 5-nitro-2-furaldehyde. The mixture then was stirred overnight at 25° and filtered to remove suspended salt. The filtrate was concentrated under reduced pressure and the residue was extracted with two 200 ml portions of ether. The combined ether extracts were concentrated to a volume of about 100 ml, diluted with an equal volume of pentane, and cooled. Filtration gave triphenylphosphine oxide. The filtrate was concentrated under reduced pressure and the residue was recrystallized from either/pentane (1:2) to give a solid, m.p.: 73°-78°. Recrystallization of the solid from either/pentane (1:4) gave 2 as yellow prisms, m.p.: 76°-78°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:24]3[CH2:26][CH2:25]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=3)=[CH:4][CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:37]([O-])=[O:38])C=1.[CH:40]1([CH:43]([OH:45])[CH3:44])[CH2:42][CH2:41]1>N1C=CC=CC=1.O.C(Cl)Cl>[CH:40]1([CH:43]([O:45][C:37](=[O:38])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:24]4[CH2:26][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=4)=[CH:4][CH:3]=2)[CH3:44])[CH2:42][CH2:41]1
Reactant: CC(O)C1CC1
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CC3)c2c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C4CC4)cc3)n(C3CC3)c2c1
Temperature: 35 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A mixture of 2-(4-aminophenyl)-1-cyclopropyl-6-(2-methoxyethoxy)indole-3-carbonitrile (35 mg, 0.1 mmol), 4-nitrophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35° C. for 2 h, followed by the addition of 1-cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 60° C. overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3×5 mL), HCl (2N, 3×5 mL), saturated NaHCO3 (3×5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano-1-cyclopropyl-6-(2-methoxyethoxy)indol-2-yl]phenyl}carbamic acid 1-cyclopropylethyl ester (22 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([CH:24]=[O:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)Nc2ncc(C=O)s2)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)Nc2ncc(CO)s2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To a suspension of 1-[(3,4-dichlorophenyl)methyl]-N-(5-formyl-1,3-thiazol-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 5) (1.2 g, 30 mmol), in a mixture of DCM/MeOH, was added sodium borohydride (130 mg). The reaction was stirred at room temperature for 1 hour. After evaporation, the residue was poured in a mixture of water/concentrated HCl solution and extracted with ethyl acetate. A solid was formed and filtered. The filtrate was dried over sodium sulphate and evaporated in vacuo. The combined solids were recrystallised from acetonitrile to give the title compound as a yellow solid (0.8 g, 67%). HRMS calculated for C15H13Cl2N5O2S (M+H)+ 398.0245, found: 398.0205, Rt: 2.59 min. MP: 170.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: Cc1cnc(NC(=O)OC(C)(C)C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution tert-butyl 5-methylpyrazin-2-ylcarbamate (500 mg, 2.39 mmol) in CCl4 (8.0 mL) were added NBS(446 mg, 2.51 mmol) and AIBN (117 mg, 0.72 mmol). The reaction mixture was stirred for 4 hours at 80° C. after which, it was partitioned between CH2Cl2 and water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (10% Ethyl acetate/Hexane) as a solvent to afford title compound (520 mg, 75% yield). 1H NMR (600 MHz, CDCl3) δ 9.29 (s, 1H), 8.95 (s, 1H), 8.37 (s, 1H), 4.38 (s, 2H), 1.57 (s, 9H). MS m/z: 288 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.CCN=C=NCCCN(C)C.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].CC(C)=O.ClCCl>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19]([NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[C:40]([O:39][CH3:38])[CH:41]=4)=[O:20])[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1onc2c1c(=O)n(-c1cccc(CC(=O)O)n1)c1cccc(Cl)c21
Reactant: COc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cccc(NC(=O)Cc2cccc(-n3c(=O)c4c(C)onc4c4c(Cl)cccc43)n2)c1
Yield: 52.6 %

Procedure:
[6-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-pyridin-2-yl]-acetic acid (0.075 g, 0.2 mmol), EDCI (0.055 g, 0.3 mmol), 3-methoxyaniline (0.03 ml, 0.26 mmol), DMAP (0.005 g, 0.04 mmol) in dichloromethane (4.5 ml) and DMP (0.75 ml) react for 5.5 h in a fashion similar to that of Example 3. Column chromatography (silica gel, acetone/dichloromethane gradient) gives the title compound (0.05 g, 53%).
Reaction SMILES: C(O[C:4]([CH:6]1[C:12](=O)[CH2:11][CH2:10][N:9]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7]1)=[O:5])C.[NH2:24][C:25]1[CH:29]=[CH:28][NH:27][N:26]=1>C(O)(=O)C>[CH2:17]([O:16][C:14]([N:9]1[CH2:8][CH2:7][C:6]2=[C:4]([OH:5])[N:26]3[C:25]([N:24]=[C:12]2[CH2:11][CH2:10]1)=[CH:29][CH:28]=[N:27]3)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCc2nc3ccnn3c(O)c2CC1
Temperature: 80 °C

Procedure:
To 5.87 g (18.38 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester in 3 mL acetic acid was added 1.53 g (18.38 mmol) 3-aminopyrazole and the reaction mixture was heated at 80° C. for 15 minutes. The resulting solid was collected by filtration and washed with TBME (3×10 mL) to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>C1COCC1>[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH:28]([OH:29])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(O)c3ccc(Cl)cc3Cl)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (76 mg, 0.427 mmol) in dry THF (4 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (0.52 mL). After 30 minutes 2,4-dichloro-benzaldehyde (60 μL) was added slowly into the reaction mixture and then stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30% ethyl acetate in hexanes to yield 4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-7-carbonitrile as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)O1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cccnc4)cc2OCC3)n(C(C)C)n1

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine to give 244. MS(ESI+) 387.2
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][O:20][CH:21]([C:26](OC)=[O:27])[C:22](OC)=[O:23].C(O)C.C[O-].[Na+]>C(O)(=O)C>[OH:23][C:22]1[C:21]([O:20][CH3:19])=[C:26]([OH:27])[N:16]=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:18][CH:17]=2)[N:15]=1
Reactant: N=C(N)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1c(O)nc(-c2ccc(OCc3ccccc3)cc2)nc1O
Temperature: 80 °C
Yield: 61.2 %

Procedure:
A mixture of 85 g of 4-benzyloxybenzamidine hydrochloride, 78.6 g of dimethyl methoxymalonate, 1700 ml of ethanol, and 187 g of sodium methylate (28% methanol solution) was heated at 80° C. for 4 hours with stirring. After cooling, 1000 ml of acetic acid was slowly added to the reaction mixture, whereupon a yellow crystal precipitated. The precipitated crystals were collected by filtration, washed twice with water until the washing became neutral, and dried at 80° C. for 3 hours in high vacuo to obtain 64.2 g (percent yield: 60.7% ) of 4,6-dihydroxy-5-methoxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:19]/[C:18](=[CH:20]\[C:21]([O:23][CH3:24])=[O:22])/[CH2:17][C@@H:16]1[C@H:25]1[O:29]C(C)(C)[N:27]([C:32](=[O:34])[CH3:33])[C@H:26]1[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=1)=O)(C)(C)C>>[ClH:1].[CH3:24][O:23][C:21](=[O:22])/[CH:20]=[C:18]1\[CH2:19][NH:15][C@@H:16]([C@@H:25]([OH:29])[C@@H:26]([NH:27][C:32](=[O:34])[CH3:33])[CH2:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=2)[CH2:17]\1
Reactant: COC(=O)/C=C1/C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)/C=C1\CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)C1
Reaction time: 8 h
Yield: 93 %

Procedure:
Add HCl 4M in dioxane (0.861 mL, 3.4 mmol) to (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-[1-methoxycarbonyl-meth-(Z)-ylidene]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.024 g, 0.046 mmol). Stir overnight. Concentrate under reduced pressure to provide the title compound (0.021 g, 93%).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:9]([CH:10]2[CH2:16][C@H:15]3[N:17]([CH2:18][CH2:19][C:20]4([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[C@H:12]([CH2:13][CH2:14]3)[CH2:11]2)[C:8]2[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=2[N:6]=1.[OH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH3:42][C:38]([CH3:43])([C:37]([N:22]1[CH2:23][CH2:24][O:25][C:20]([CH2:19][CH2:18][N:17]2[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[CH2:16][CH:10]([N:9]2[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[N:6]=[C:5]2[CH3:4])[CH2:11]3)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)=[O:36])[CH2:39][OH:40]
Reactant: CC(C)(CO)C(=O)O
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CNCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)C(C)(C)CO)CCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
To a stirred solution of 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihyrdochloride (59.3 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), and diisopropylethylamine (70 μL, 0.40 mmol) in 1 mL DMF was added HATU (57 mg, 0.15 mmol). The resulting mixture was stirred at ambient temperature for 24 h and then diluted with methylene chloride and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), concentrated by evaporation, and purified by chromatography (5% (2M NH3/MeOH) in CHCl3) to afford 2,2-dimethyl-3-(2-{2-[(1R,5S)-3(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol (29.3 mg. 55%) as amorphous solid. 1H NMR (400 MHz, CDCl3), δ 7.65 (m, 1H), 7.44-7.26 (m, 6H), 7.19-7.10 (m, 2H), 4.80 (br., 1H), 4.69 (m, 1H), 3.75-3.37 (m, 8H), 3.35-3.16 (m, 3H), 2.58 (s, 3H), 2.46-2.34 (m, 2H), 2.13-1.84 (m, 8H), 1.68-1.59 (m, 2H), 1.23 (s, 3H), 1.02 (s, 3H); ESI-MS 531 (M+H), 553 (M+Na).
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrC/C=C/c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CBr)C1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.4 %

Procedure:
To a solution of [(E)-3-bromo-1-propenyl]benzene (705 mg, 3.58 mmol) in dichloromethane (1 ml) was added rhodium (II) acetate dimer (20 mg, 0.05 mmol). To the mixture was added dropwise at room temperature over 4 h a solution of ethyl diazoacetate (0.43 ml, 0.47 g, 4.15 mmol) in dichloromethane (2.5 ml). The mixture was stirred at room temperature for 60 h. The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (75 mg, 8%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]=[N+:12]=[N-:13])=[N:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:5])C.O1CCCC1.O.[OH-].[Li+]>O.C(OCC)C>[N:11]([C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=[N+:12]=[N-:13]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.4 %

Procedure:
To a mixture of 2.44 g (7.14 mmole) of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and 45 mL of tetrahydrofuran was added, 3.01 g (71.5 mmole) of lithium hydroxide monohydrate in 33 mL of water. The mixture was stirred at room temperature for 17 hours and then diluted with 300 mL of diethyl ether. The ether layer was extracted three times with 100 mL of water. The combined aqueous phases were acidified by the addition of 1M hydrochloric acid and extracted three times with 100 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.76 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid as a light yellow solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O.[Cl-].[Ca+2].[Cl-].C(O)C.Cl>[Fe].O>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15]
Reactant: O=[N+]([O-])c1cccc2cc(C3=NCCS3)[nH]c12
Agent: [Fe]
Agent: Cl
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: Nc1cccc2cc(C3=NCCS3)[nH]c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a mixture of 2-(4,5-dihydro-1,3-thiazol-2-yl)-7-nitro-1H-indole (4.0 g), iron powder (4.0 g), calcium chloride (770 mg), ethanol (45 mL) and water (5 mL) was added 1N hydrochloric acid (0.2 mL), and the mixture was stirred at 80° C. for 2 hr. After cooling the reaction mixture to room temperature, and the insoluble material was filtered off. Saturated aqueous sodium hydrogen carbonate was added to the filtrate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate) to give the title compound (1.9 g, yield 56%) as pale-yellow crystals.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[O:6][C:7]([C:9]1[C:13]([NH:14][C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:21][CH:20]=[C:19]([CH:30]3[CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=1)=O>>[CH:1]1([NH:4][C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[C:22]([NH:23][C:24]4[CH:25]=[N:26][CH:27]=[N:28][CH:29]=4)=[CH:21][CH:20]=[C:19]([CH:30]4[CH2:32][CH2:31]4)[N:18]=3)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NC1CC1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CC2)n1
Yield: 24 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclopropylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (24%) as amorphous yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10][CH2:11]2)[CH:16]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1cccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
126.1 mg of the target compound (0.35 mmol, 42.9%) was obtained using 1-(3-methoxyphenyl)piperazine (315 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.