Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:30]=2)[CH2:25][CH2:24][C:23]1=[O:41].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=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:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[N:22]([CH3:21])[C:23](=[O:41])[CH2:24][CH2:25]3)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2cc(-c3cncc(OC[C@@H]4CCN4C(=O)OC(C)(C)C)c3)ccc21
Temperature: 110 °C
Yield: 86.1 %

Procedure:
A sealed tube was charged with (S)-2-(5-bromo-pyridin-3-yloxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (intermediate A-26, 0.260 g, 0.76 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1, 0.239 g, 0.83 mmol) and DMF (3 mL). Then, bis(triphenylphosphine)palladium(II)chloride (0.053 g, 0.076 mmol), followed by 1N aqueous Na2CO3 solution (2.27 mL, 2.27 mmol) were added and the reaction was heated to 110° C. (pre-heated oil bath) for 1 h. The mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (20 mL). The resulting filtrate was poured into aq. NaHCO3 (20 mL) and the aqueous layer was extracted with EtOAc (20 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.277 g, 86%) as a light brown foam. MS: 424.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[CH2:21][N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:37]([CH3:36])(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CNc3ccccc3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A 250-mL round-bottomed flask was charged with N-(((2S)-1,4-dibenzyl-2-piperazinyl)methyl)aniline (0.734 g, 1.98 mmol), DMAP (0.027 g, 0.22 mmol), triethylamine (0.85 mL, 6.1 mmol) and CH2Cl2 (8 mL). Methanesulfonyl chloride (0.23 mL, 3.0 mmol) was added drop wise at room temperature and the mixture was stirred at room temperature for 2 h. Additional methanesulfonyl chloride (0.20 mL, 2.6 mmol) and triethylamine (1.0 mL, 7.2 mmol) were added. The mixture was stirred at room temperature for another 1.5 h and then the mixture was concentrated to half the original volume and partitioned between water (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 0 to 60% EtOAc in hexanes) to afford N-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.528 g) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1C(=O)OC
Yield: 97.4 %

Procedure:
A mixture of dimethyl-4-nitrophthalate (15.0 g, 62.7 mmol) and 10% Pd—C (1.5 g) in ethyl acetate (100 mL) was hydrogenated at 50 psi overnight. The reaction mixture was filtered through Celite, and the filter was washed with additional ethyl acetate (50 mL). The solvent was evaporated, and the residue was stirred in hexanes. The solid was filtered, washed with additional hexanes and dried to give 12.77 g of 4-amino-phthalic acid dimethyl ester as a pale orange solid, in 97% yield; 1H NMR (DMSO-d6) δ 3.71 (s, 3H), 3.75 (s, 3H), 6.17 (s, 2H), 6.58-6.65 (m, 2H), 7.57 (d, J=8.4 Hz, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([S:16][C:17]1[CH:18]=[C:19]([C:23]2[O:28][C:27](=[O:29])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=2)[CH:20]=[CH:21][CH:22]=1)([F:15])[F:14]>C(Cl)Cl>[F:15][C:13]([F:12])([F:14])[S:16]([C:17]1[CH:18]=[C:19]([C:23]2[O:28][C:27](=[O:29])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=2)[CH:20]=[CH:21][CH:22]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1oc(-c2cccc(SC(F)(F)F)c2)nc2ccccc12
Solvent: ClCCl
Product: O=c1oc(-c2cccc(S(=O)C(F)(F)F)c2)nc2ccccc12
Reaction time: 22 h

Procedure:
8.85 Parts by weight of m-chloroperbenzoic acid in 150 parts of methylene chloride are added to a mixture of 16.2 parts of 2-(m-trifluoromethylmercapto-phenyl)-3,1-benzoxazin-4-one and 130 parts of methylene chloride at room temperature. The mixture is then stirred for a further 22 hours. The precipitate which has formed is dissolved by adding 100 parts of methylene chloride and the solution obtained is extracted twice with 0.3 N sodium hydroxide solution and with water. It is then dried over magnesium sulfate and chromatographed over aluminum oxide, giving 12.4 parts of 2-(m-trifluoromethylsulfinyl-phenyl)-3,1-benzoxazin-4-one, of melting point 106°-108° C.
Reaction SMILES: CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[NH:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:19]([C:30]([OH:32])=O)[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.[NH2:40][C@H:41]([C:57]([O:59][CH3:60])=[O:58])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].Cl>CN(C=O)C.CCOC(C)=O.C(OCC)C>[NH:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:19]([C:30]([NH:40][C@H:41]([C:57]([O:59][CH3:60])=[O:58])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])=[O:32])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 16 h

Procedure:
9.8 ml NEt3, 11.8 g HOBT and 21.3 g BOC-(D)Trp-OH are added to 23.3 g H-Lys(Z)-OMe hydrochloride in 300 ml DMF, and the solution cooled to -15° C. 15.6 g DDCI in 50 ml DMF are added and the reaction mixture stirred for ca. 16 hrs. at 0° C., followed by 2 hrs. at room temperature. The reaction mixture is diluted with AcOEt/ethyl-ether and the dicyclohexyl-urea is filtered off. The filtrate is washed with 2 N citric acid, H2O, 10% KHCO3 solution and 30% NaCl solution. The organic phase is dried over Na2SO4 and concentrated strongly under vacuum. Crystallisation is effected by the addition of ethyl-ether/hexane and the product is filtered off, washed with ethyl-ether/hexane and dried to yield the title compound:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[C:28]([O:36][CH3:37])=[N:29][CH:30]=[CH:31][C:32]=1B(O)O>CN(C=O)C>[Cl:26][C:27]1[C:28]([O:36][CH3:37])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: COc1nccc(B(O)O)c1Cl
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Solvent: CN(C)C=O
Product: COc1nccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3-chloro-2-methoxypyridine-4-boronic acid (CAS RN 957060-88-7) and using DMF as solvent. Pale yellow sticky solid (11%). MS (ESI): m/z=489.9 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]2[S:8][CH:9]=[CH:10][C:4]2=[N:3]1.C([Li])CCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]2[S:8][C:9]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:4]2=[N:3]1
Reactant: Cc1c2sccc2nn1C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2nn(C)c(C)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a cold (−78° C.) mixture of 2,3-dimethyl-2H-thieno[3,2-c]pyrazole (400 mg, 2.63 mmol) and THF (15 mL) under a nitrogen atmosphere was added n-butyllithium (1.156 mL, 2.89 mmol) dropwise. The reaction mixture was stirred at −78° C. for 60 minutes. Tributylchlorostannane (0.855 mL, 3.15 mmol) was added, and the reaction mixture was stirred at −78° C. for 60 minutes and then warmed to room temperature with stirring over a period of 1 hour. The reaction mixture was quenched with brine (15 mL) and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and evaporated. The resulting residue was purified by silica gel column (80 g) chromatography, eluting with a gradient of 0-100% hexane and EtOAc. The pure product fractions were combined and evaporated to give the title compound as a gray solid (1.060 g, 2.402 mmol, 91%). 1H NMR (400 MHz, CDCl3) δ ppm 0.78-0.99 (m, 9H), 1.06-1.22 (m, 6H), 1.23-1.46 (m, 6H), 1.48-1.70 (m, 6H), 2.46 (s, 3H), 3.96 (s, 3H), 7.03 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H34N2SSn, 443. found, 443.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[CH:22][CH:21]=[CH:20]3)=[N:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:15])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)nc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(-n2cccc2)nc1

Procedure:
A mixture of 1.0 g. (5 mmole) 4,5-dihydro-5-methyl-6-(2-amino-5-pyridyl)-3(2H)-pyridazinone, 0.66 g. (5 mmole) 2,5-dimethoxytetrahydrofuran and 15 ml. acetic acid was heated under reflux for 30 minutes. The reaction mixture was evaporated, the residue was taken up in dichloromethane, washes with an aqueous solution of sodium hydrogen carbonate, evaporated and the residue chromatographed on silica gel (elution agent: trichloromethane/methanol 19:1 v/v). There were obained 0.5 g. of the title compound (39% of theory); m.p. 192°-193° C., after recrystallisation from diethyl ether.
Reaction SMILES: C[Si](C)(C)Cl.[I-].[Na+].C(#N)C.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([F:34])[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20][CH2:19]1>C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([F:34])[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: O=C(OCc1ccccc1)N1CCC(F)(c2ccccc2Cl)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC1(c2ccccc2Cl)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
1.53 mL of trimethylchlorosilane and 1.82 g of sodium iodide were added to acetonitrile (50 mL) solution of 2.11 g of benzyl 4-(2-chlorophenyl)-4-fluoropiperidine-1-carboxylate, and stirred at room temperature for 30 minutes. 0.77 mL of trimethylchlorosilane and 0.91 g of sodium iodide were further added thereto, and stirred for 10 minutes. Then, the reaction liquid was diluted with ethyl acetate, and back-extracted with 1 M hydrochloric acid. Sodium hydroxide was added to the aqueous layer so that the system was made basic, and then extracted with chloroform, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (chloroform/methanol=10/1) to obtain 992 mg of the entitled compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[C:5]#[C:6][CH:7]([OH:10])[CH2:8][CH3:9])[CH3:2]>ClCCl.O=[Mn]=O>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[C:5]#[C:6][C:7](=[O:10])[CH2:8][CH3:9])[CH3:13]
Reactant: CCOC(C#CC(O)CC)OCC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(C#CC(=O)CC)OCC
Yield: 34.3 %

Procedure:
6,6-Diethoxy-hex-4-yn-3-ol (4.30 g, 23.1 mmol) was dissolved in dichloromethane (200 ml) and treated with activated MnO2 (50 g) at rt for 15 h. The reaction mixture was filtered through a plug of celite and Na2SO4. The filtrated was concentrated under reduced pressure and purified by flash chromatography with 0-20% EtOAc in hexane to afford the desired product (1.46 g, 34% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1)(=[O:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(#N)C>[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[CH:34][C:33]([F:50])=[CH:32][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc3c(c2)CCN(C2COC2)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(c3)CCN(C3COC3)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 45.1 %

Procedure:
A 15 mL microwave reaction vial with a magnetic stirrer was charged with 258c (0.39 g, 1 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (0.48 g, 1 mmol), potassium phosphate (0.54 g, 2 mmol), sodium acetate (0.17 g, 2 mmol), acetonitrile (10 mL), water (1 mL), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.08 g, 0.1 mmol). The reaction mixture was heated at 110° C. for 2 hours under argon atmosphere. After this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 40:1 dichloromethane/methanol to give 258d (0.3 g, 50%). LC/MS: m/z 666 (M+H)+
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)s1
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
Sodium hydride (60%, 1.2 g, 30 mmol) is added to a solution of 4-chlorothiophenol (4.3 g, 30 mmol) in THF (30 mL). The resulting solution is stirred for 10 minutes then the solvent is removed in vacua. Acetone (60 mL) is added followed by 5-bromothiophene-2-carboxaldehyde (3.0 mL, 25 mmol). The mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the resulting slurry diluted with CH2Cl2. This solution is washed three times with 1N NAOH then dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by flash column chromatography (gradient of 1 to 5% EtOAc in heptane) to give the desired product (6.2g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.13, 7.31-7.39, 7.63, 9.78.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH:13]3[CH2:14][N:9]([C:10]4[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:11]=4[CH2:12]3)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH:1]1([C:4]([N:6]2[CH:13]3[CH2:14][N:9]([C:10]4[CH:18]=[C:17]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:15][C:11]=4[CH2:12]3)[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: Nc1ccc2c(c1)N1CCN(C(=O)C3CC3)C(C2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)N1CCN(C(=O)C3CC3)C(C2)C1
Reaction time: 3 h

Procedure:
A mixture of 4-cyclopropanecarbonyl-9-amino-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (8 g.) and acetic anhydride (50 ml.) was heated on a steam bath for two hours. Pyridine was added and heating was continued for three hours. The mixture was concentrated to dryness. The residue was partitioned between aqueous base and chloroform. The chloroform layer was dried and concentrated to dryness. Recrystallization of the residue from acetonitrile afforded a product (m.r. 117°-187° C.), which to remove product of diacetylation was warmed with dilute aqueous sodium bicarbonate. Extraction of the resulting mixture with chloroform and concentration of the chloroform extract to dryness afforded 4-cyclopropanecarbonyl-9-acetamido-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (about 8 g.), the compound of Formula VI wherein Q' is cyclopropanecarbonyl and R"CONH is acetamido.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:39]3[CH2:38][CH2:37][N:36]([C:33]4[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=4)[CH2:41][CH2:40]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 72.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (511 mg, 1.33 mmol, 72%) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)[CH:2](C)[CH3:3].C(OC(=O)C1C=C(C)C(Cl)=NC=1)C.C(/B(O)O)=C\C>>[CH3:14][C:13]1[C:5]([CH2:1][CH2:2][CH3:3])=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: Cc1cc(C(=O)O)cnc1CC(C)C
Agent: C/C=C/B(O)O
Agent: CCOC(=O)c1cnc(Cl)c(C)c1
Product: CCCc1ncc(C(=O)O)cc1C

Procedure:
5-Methyl-6-propyl-nicotinic acid (1.85 g as hydrochloride) is prepared in analogy to 6-isobutyl-5-methyl-nicotinic acid from 6-chloro-5-methyl-nicotinic acid ethyl ester (2.0 g) and commercially available trans-1-propen-1-yl boronic acid (1.3 g); 1H NMR (D6-DMSO) δ 0.96 (t, J=7.3 Hz, 3H), 1.72 (m, 2H), 3.05 (t, J=7.5 Hz, 2H), 8.66 (m, 1H), 8.86 (d, J=1.5 Hz, 1H).
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:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[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:19]=[C:20]([C:21]([N:39]4[CH2:40][CH2:41][CH2:42][CH:38]4[C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: c1cncc(C2CCCN2)c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCCC1c1cccnc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(3-pyridinyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=577.95 (M+H+); retention time=0.65 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4]([NH:13][C:14]([NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:3]=1.O.[NH2:26][NH2:27]>CCO>[NH2:9][C:8]1[C:7]2[C:6]([CH2:10][O:11][CH3:12])=[N:5][C:4]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:3][C:2]=2[NH:27][N:26]=1
Reactant: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12

Procedure:
A solution of (R)-1-(4-chloro-5-cyano-6-(methoxymethyl)pyridin-2-yl)-3-(1-phenylethyl)urea (151.4 mg, 0.439 mmol) and hydrazine hydrate (75 μl, 1.546 mmol) in EtOH (4 ml) was heated to 100° C. in a sealed vial for 18 hr. The mixture was concentrated in vacuo and purified via flash chromatography (0-20% MeOH/EtOAc) to provide (R)-1-(3-amino-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd for C17H21N6O2 [M+H]+ 341. found 341. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.97 (s, 1H), 7.33 (m, 4H), 7.22 (m, 1H), 7.14 (s, 1H), 5.35 (s, 2H), 4.85 (t, J=7.1, 1H), 4.65 (m, 2H), 3.31 (s, 3H, overlaps with H2O peak), 3.15 (d, J=5.1 Hz, 1H), 1.39 (d, J=7.1 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH2:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11].C([BH3-])#N.[Na+].C(N(CC)CC)C>CCCCCC.C(OC(=O)C)C>[CH2:1]([NH:8][CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH:10]([CH3:11])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)CC(C)C
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC(CC(C)C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Benzylamine (3.1 ml, 28 mmol) was added to a stirred mixture of 2-methyloctan-4-one (4.0 g, 28 mmol) and 3A molecular sieves in dry, methanol (40 ml) under argon. The mixture was stirred at room temperature overnight. Sodium cyanoborohydride (1.77 g, 28 mmol) was added and the mixture stirred overnight. Stirring was stopped and the solution was decanted, from the molecular sieves, into saturated aqueous ammonium chloride. The mixture was filtered, concentrated, ethyl acetate added and the mixture washed with water. The organics were dried over anhydrous magnesium sulphate, filtered and concentrated to give a yellow oil. Chromatography (silica: 1% triethylamine and 10% ethylacetate in hexane) gave N-benzyl -2-methyl-4-aminooctane (3.0 g, 46%) as a yellow oil.