Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C>[C:15]1([C:2]2[C:3]3[O:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ncnc2c1oc1ccccc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1ccc(-c2ncnc3c2oc2ccccc23)cc1
Yield: 45 %

Procedure:
First, 2.42 g of 4-chlorobenzofuro[3,2-d]pyrimidine, 2.19 g of phenylboronic acid, 1.89 g of sodium carbonate, 0.10 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was heated by 60-minute microwave irradiation (2.45 GHz, 100 W). After that, the obtained residue was suction-filtered with water and washed with hexane. The obtained solid was purified by flash column chromatography using a developing solvent in which the ratio of hexane to ethyl acetate was 2:1, so that Hpbfpm, which was the pyrimidine derivative to be produced, was obtained as a white powder in a yield of 45%. Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is illustrated in (d-1) below.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[OH:23][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3OC)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1-c1nc2cnc(C(=O)NCC(=O)O)c(O)c2s1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixture of 7-hydroxy-2-(2-methoxy-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (120 mg, 0.36 mmole) and glycine (546 mg, 7.27 mmole) in 0.5 M sodium methoxide/methanol (13.8 ml, 6.91 mmole) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (25 ml) and extracted with methyl tert-butyl ether (2×25 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl (9 ml). The resulting jelly was extracted with dichloromethane and ethyl acetate. The organic layer was combined, washed with brine and dried in vacuo to give the title compound as a yellow solid (94 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.39 (br s, 1H), 8.88 (s, 1H), 8.45 (d, 1H), 7.62 (m, 1H), 7.33 (d, 1H), 7.18 (t, 1H), 4.01 (s, 3H), 4.03 (d, 2H); MS: (+) m/z 360.25 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][CH:5]=[CH:6][C:7](=[O:9])[N:8]=1.C1C(=O)N([I:17])C(=O)C1>CN(C=O)C.O>[I:17][C:6]1[C:7](=[O:9])[N:8]=[C:3]([O:2][CH3:1])[NH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(=O)cc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(=O)c(I)c[nH]1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
2-Methoxypyrimidin-4(1H)-one (1.00 g, 7.93 mmol) and n-iodosuccinimide (3.57 g, 15.86 mmol) were mixed in DMF (8 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 70° C. for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting solid was suspended in DCM, filtered, and washed with DCM to give 5-iodo-2-methoxypyrimidin-4(1H)-one. [M+1]=252.9.
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][C:13]=1[CH2:14][NH2:15].[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=3)[C:36](O)=[O:37])[C:29]2=[O:42])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=3)[C:36]([NH:15][CH2:14][C:13]3[S:12][C:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:10][C:9]=3[CH3:8])=[O:37])[C:29]2=[O:42])=[CH:43][CH:44]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: Cc1nc(-c2ccccc2)sc1CN
Agent: NCc1cocn1
Product: Cc1nc(-c2ccccc2)sc1CNC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 53 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (4-methyl-2-phenylthiazol-5-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((4-methyl-2-phenylthiazol-5-yl)methyl)isonicotinamide was obtained as a colorless solid in 53% yield: mp 182-184° C.; 1HNMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 7.87-7.84 (m, 2H), 7.42-7.37 (m, 4H), 7.24-7.20 (m, 2H), 7.03-6.93 (m, 3H), 4.75 (d, J=5.7 Hz, 2H), 4.40 (s, 2H), 4.02 (t, J=8.1 Hz, 2H), 3.35 (t, J=8.1 Hz, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1, 165.6, 164.0, 160.7, 157.0, 153.0, 151.1, 148.5, 142.4, 133.6, 132.0, 129.9, 129.8, 128.9, 127.7, 126.4, 116.0, 115.8, 115.6, 109.0, 47.2, 41.3, 41.0, 35.8, 15.3; MS (ES+) m/z 501.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[C:24](=[CH:19][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[C:7](=[O:18])[C:6]=3[C:2]=1[CH3:1])[C:25](=[O:31])[NH:26]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 74.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-bromo-1,3-dihydro-indol-2-one (prepared according to US20030225127) as starting materials to give 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (44 mg, 74.4%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.Br[C:27]1[N:28]=[CH:29][S:30][C:31]=1[NH:32][C:33](=[O:35])[CH3:34]>CN(C=O)C.[Cu]I>[CH3:1][C:2]1[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[N:5]([C:27]2[N:28]=[CH:29][S:30][C:31]=2[NH:32][C:33](=[O:35])[CH3:34])[CH:6]=1
Reactant: CC(=O)Nc1scnc1Br
Reactant: CCCc1nc(C)c[nH]1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCc1nc(C)cn1-c1ncsc1NC(C)=O
Temperature: 90 °C

Procedure:
A flask was charged with 4-methyl-2-propyl-1H-imidazole from example 1.6 (140 mg, 1.13 mmol), Cs2CO3 (1.10 g, 3.39 mmol) and copper (I) iodide (108 mg, 0.56 mmol). A solution of (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (80 mg, 0.56 mmol,) and N-(4-bromothiazol-5-yl)acetamide from example 1.5 (250 mg, 1.13 mmol) in DMF (30 mL) was added under N2. The mixture was heated at 90° C. for overnight. It was concentrated and directly used for the next step without further purification.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C(N(CC)CC)C>O1CCCC1>[C:1]12([C:11]([O:17][CH2:16][C:15]([Br:14])([F:19])[F:18])=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OCC(F)(F)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCC(F)(F)Br)C12CC3CC(CC(C3)C1)C2

Procedure:
In tetrahydrofuran, 1-adamantanecarbonyl chloride and 2-bromo-2,2-difluoroethanol were mixed and ice cooled. Triethylamine was added to the mixture. By standard separation operation and solvent distillation, 2-bromo-2,2-difluoroethyl 1-adamantanecarboxylate was obtained. This compound was converted into a sodium sulfinate with sodium dithionite and then oxidized with hydrogen peroxide, yielding the target compound, sodium 2-(1-adamantanecarbonyloxy)-1,1-difluoroethane-sulfonate.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[S:34]1[CH:39]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41](O)=[O:42])[S:37][CH2:36][CH2:35]1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[S:34]1[CH:39]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([NH:2][CH:3]2[C:24](=[O:25])[N:5]3[C:6]([C:11]([O:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]23)=[O:42])[S:37][CH2:36][CH2:35]1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CON=C(C(=O)O)C1=CSCCS1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)C1=CSCCS1
Yield: 89.4 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (4.06 g.) and trimethylsilylacetamide (9.19 g.) in ethyl acetate (40 ml.) and a solution of 2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 2.2 g.), N,N-dimethylformamide (0.8 g.) and phosphoryl chloride (1.67 g.) in ethyl acetate (24 ml.) were treated in a similar manner to that of Example 19-(1) to give 4-nitrobenzyl 7-[2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.1 g.).
Reaction SMILES: [CH3:1][NH:2][C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(#N)C>[NH2:14][C:13]1[C:10]([C:11]#[N:12])=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]([CH3:1])[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CBr
Reactant: CNC(=C(C#N)C#N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(N)c(C#N)c(-c2ccccc2)n1C
Temperature: 25 °C
Yield: 56 %

Procedure:
[(Methylamino)phenylmethylene]methane-1,1-dicarbonitrile (3.00 g) and anhydrous potassium carbonate (4.51 g) were added to acetonitrile (200 mL). A solution of methyl bromoacetate (3.09 mL) in acetonitrile (10 mL) was added thereto, and the mixture was heated to reflux for 3 hours. After cooling the mixture to room temperature, it was allowed to stand, the supernatant was separated by decantation, and the solvent was distilled off under reduced pressure. The concentrated residue was combined with the solid portion remaining after decantation, ethyl acetate and water were added, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized (hexane/ethyl acetate=1/1) to obtain the title compound (1.15 g) as a white solid. The recrystallized residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→2/1) to obtain the title compound (1.21 g, (total of 2.36 g with the recrystallized portion), yield: 56%) as a white solid. The NMR and ESI/MS data for this compound are shown below.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:9]([SH:12])[CH2:10][CH3:11]>>[CH2:7]([O:6][C:1](=[O:5])[CH2:2][CH:3]([S:12][CH2:9][CH2:10][CH3:11])[CH3:4])[CH3:8]
Reactant: C/C=C/C(=O)OCC
Reactant: CCCS
Product: CCCSC(C)CC(=O)OCC
Temperature: 30 °C

Procedure:
Into a 500 ml one neck flask equipped with reflux condenser, spin bar, and hot plate containing a built in magnetic stirrer, cooling bath and ultra-violet light source are placed 17.9 grams (0.157 moles) of ethyl crotonate and 12 grams (0.158 moles) of n-propyl mercaptan with stirring and maintaining the temperature at 30° C., the reaction mass is stirred after turning the ultraviolet light on. The reaction mass is continued to be stirred for a period of 8 hours. At the end of the 8 hour period, the ultra-violet light was turned off and the reaction mass is transferred to a distillation flask and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: CS([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=O)=O.[CH:16]1([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:26][C:25]=2[F:38])=[O:22])[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:16]1([NH:20][C:21](=[O:22])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH2:5][C:6]4[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=4)[C:9]([O:11][CH3:12])=[O:10])[CH2:34][CH2:33]3)=[O:31])=[CH:26][C:25]=2[F:38])[CH2:17][CH2:18][CH2:19]1
Reactant: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1F)NC1CCC1
Reactant: COC(=O)c1ccnc(CS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccnc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2)c1
Yield: 58.6 %

Procedure:
Methyl 2-(methylsulfonylmethyl)isonicotinate (2.99 mmol, 0.686 g), 1-cyclobutyl-3-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)urea (2.99 mmol, 0.959 g) and potassium carbonate (8.98 mmol, 1.241 g) were combined and heated to 40° C. in acetonitrile (20 mL) for 2 hours. The reaction mixture was concentrated at reduced pressure and the residue taken up in dichloromethane. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (822 mg). MS (ESI) m/z 470.5 [M+H]+
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30]>>[CH3:28][S:29]([CH2:32][CH2:33][NH:34][C:22]([C:19]1[CH:20]=[CH:21][C:16]2[O:15][CH2:14][CH2:13][N:12]3[CH:25]=[C:9]([C:8]4[N:4]([CH2:3][C:2]([F:27])([F:26])[F:1])[N:5]=[CH:6][N:7]=4)[N:10]=[C:11]3[C:17]=2[CH:18]=1)=[O:23])(=[O:31])=[O:30]
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2

Procedure:
Following the procedure for 109, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-(methylsulfonyl)ethanamine gave 119. MS: (ESI+)=485.1. 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=2.1 Hz, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.10 (s, 2H), 7.78 (dd, J=8.6, 2.2 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 5.94 (q, J=8.9 Hz, 2H), 4.58 (s, 4H), 3.69 (dd, J=12.7, 6.5 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 3.04 (s, 3H)
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.C([BH3-])#[N:45].[Na+]>C(OCC)(=O)C>[NH2:45][CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=3)([CH3:39])[CH3:38])=[CH:23][N:22]=2)[CH2:25][CH2:26]1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCC(=O)CC2)cc1-c1ccccc1Cl
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCC(N)CC2)cc1-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
To a solution of 752 mg (1.26 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(2-chloro-phenyl)-4-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 7 ml methanol 970 mg (12.6 mmol) ammonium acetate were added at room temperature. The mixture was stirred 5 minutes at this temperature, cooled to 0° C. and treated with 119 mg (1.89 mmol) sodium cyanoborohydride. The reaction mixture was allowed to slowly warm to room temperature during 5 h, followed by dilution with 20 ml ethyl acetate, washing with 10 ml brine and extraction with 20 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 480 mg (64%) of the title compound as a white foam.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].Cl.[CH3:7][N:8]([CH3:16])[C:9]1[S:10][CH:11]=[C:12]([CH2:14]Cl)[N:13]=1>Cl>[CH3:7][N:8]([CH3:16])[C:9]1[S:10][CH:11]=[C:12]([CH2:14][S:5][CH2:4][CH2:3][NH2:2])[N:13]=1
Reactant: NCCS
Reactant: CN(C)c1nc(CCl)cs1
Agent: Cl
Product: CN(C)c1nc(CSCCN)cs1

Procedure:
Cysteamine hydrochloride (5.24 g; 45.9 mmoles) and 2-dimethylamino-4-chloromethylthiazole hydrochloride (9.8 g; 45.9 mmoles) [prepared from N,N-dimethylthiourea and 1,3-dichloro-2-propanone] were dissolved in 45 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 100° for 96 hours. The mixture was evaporated under reduced pressure and the residue made basic with 40% aqueous NaOH. The aqueous phase was extracted with methyl acetate, dried and evaporated to give the title compound as an oil which was used without further purification in Step B.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl[C:56]1[S:57][C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[S:57]1[C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=[C:56]1[N:50]1[CH2:51][CH2:52][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48][CH2:49]1
Reactant: Clc1nc2ccccc2s1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(c2nc3ccccc3s2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 11 %

Procedure:
A solution of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) (10 mg, 0.0144 mmol), 2-chloro-benzothiazole (20.7 mg, 0.122 mmol) was heated at 80° C. for 1 hour. Then the solution was diluted with MeOH and purified on LC/MS using pH2 buffer to give the desired compound in 11% yield. LCMS for C31H30ClN8OS (M+H)+: m/z=597.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[CH3:9][C:10](C)([O-:12])[CH3:11].[K+]>CC(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:12][CH:10]([CH3:11])[CH3:9])[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1cc(Br)ccn1
Temperature: 80 °C

Procedure:
To the stirred solution of 4-bromo-2-fluoro-pyridine 17BV (4.12 g, 23.41 mmole) in 50 mL anhydrous IPA in a 150 mL pressure vessel was added 2.627 g (23.41 mmole) of solid potassium tert-butoxide under dry N2 gas. The pressure vessel was tightly sealed and heated at 80° C. for 3 hours. The pressure vessel was cooled to 0° C. in ice-bath before opening. The contents of the pressure vessel were transferred to 250 mL RBF and concentrated to a small volume. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated and resulting clear oil was purified on RediSep 80 g cartridge eluting with 20:1 Hexanes/EtOAc to give clear oil 18BV (4.2 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
In a 60-mL vial, tert-butyl-4-bromobenzylcarbamate (1.25 g, 4.37 mmol) was dissolved in DMF (12 mL). To this solution was added Ag2O (4.0 g, 17 mmol) followed by the addition of CH3I (0.68 mL, 11 mmol). The mixture was stirred at 50° C. for 18 hours. The reaction mixture was filtered through a bed of celite and the celite was washed with methanol (2×20 mL) and dichloromethane (2×20 mL). The filtrate was concentrated to remove most of the DMF. The residue was treated with water (50 mL) and a white emulsion formed. This mixture was extracted with ethyl acetate (4×25 mL), dried over Na2SO4, and the solvent was evaporated to yield tert-butyl-4-bromobenzyl(methyl)carbamate (1.3 g, 98%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1([CH2:32][O:33][CH3:34])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2([CH2:32][O:33][CH3:34])[CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: COCC1(CBr)CC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: COCC1(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 1-bromomethyl-1-methoxymethyl-cyclopropane (described in WO 2001032633) gave the title compound. ES-MS m/e (%): 465.5 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][CH:5]([CH:8]([CH2:14][N+:15]([O-])=O)[CH2:9][C:10](OC)=[O:11])[CH2:4][CH2:3]1>CO.[Ni]>[F:1][C:2]1([F:18])[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:14][NH:15][C:10](=[O:11])[CH2:9]2)[CH2:4][CH2:3]1
Reactant: COC(=O)CC(C[N+](=O)[O-])C1CCC(F)(F)CC1
Agent: [Ni]
Solvent: CO
Product: O=C1CC(C2CCC(F)(F)CC2)CN1
Temperature: 50 °C

Procedure:
Methyl 3-(4,4-difluorocyclohexyl)-4-nitrobutanoate a1-20 (1.390 g, 5.24 mmol, 1 eq) is dissolved in methanol (35 ml) and Raney Nickel (50% in water, 200 mg, 1.7 mmol, 0.3 eq) is rinsed 3 times with methanol and added to the solution. The mixture is heated overnight at 50° C. under a H2 atmosphere (20 bars). The mixture is then filtered and the filtrate is evaporated under reduced pressure to afford 4-(4,4-difluorocyclohexyl)pyrrolidin-2-one a1-26.