Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19](O)=[O:20].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:19]([C:3]1[C:4]([CH:16]([CH3:18])[CH3:17])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:20]
Reactant: Nc1nccs1
Reactant: CC(C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of 6.3 g of the product of Step E, 2.1 g of 2-aminothiazole, 4.74 g of dicyclohexylcarbodiimide and 130 ml of dimethylformamide was stirred for 72 hours and was then filtered. The filtrate was evaporated to dryness and the residue was taken up in 50 ml of a 5% sodium bicarbonate solution. The mixture was filtered and washed with water until the wash water were neutral to obtain 8 g of raw product. The latter was chromatographed and was eluted with a 9-1 methylene chloride-ethyl acetate to recover the fraction with an Rf = 0.25. The product was dried to obtain 6 g of product which was crystallized from acetone to obtain 4.2 g of N-(3-thiazolyl)-4-hydroxy-2-isopropyl-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 213° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C(NC1SC(/C=C\C(OCC)=O)=C(CCC2C=CC(NC(OC(C)(C)C)=O)=CC=2)N=1)(=O)C.[H][H]>[Pd].C1COCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)/C=C\c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1

Procedure:
A mixture of ethyl(2E)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylate and ethyl(2Z)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]acrylate (200 mg), THF (7 ml) and 10% Pd/C (392 mg) were combined under nitrogen atmosphere. The mixture was stirred under 3 atm hydrogen atmosphere at 20° C. for 3 h. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give ethyl 3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazol-5-yl]propanoate as a colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.ClC1C=C(C(OO)=[O:22])C=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]23[O:22][CH:9]2[CH2:10][O:11][CH2:12][CH2:13]3)=[N:6][CH:7]=1
Reactant: Brc1cnc(C2=CCOCC2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Brc1cnc(C23CCOCC2O3)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
Compound i (105 mg; 0.436 mmol) was dissolved in DCM (15 mL) and cooled to 0° C., then solid 3-chlorobenzenecarboperoxoic acid (280 mg, 1.14 mmol) was added and the mixture stirred overnight. The mixture was quenched with 1M Na2S2O3 (aq) (5 mL), washed with sat. NaHCO3 (aq) (3×30 mL) followed by brine (1×30 mL). The organic fraction was dried (MgSO4). Purification by chromatography on silica eluting with 0-50% EtOAc-n-heptane gave ii (20 mg, 18%). MS: 256.9 & 258.8; 1:1 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C-:20]#[N:21].[Na+]>CN(C=O)C.C(OCC)C>[OH:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:20]#[N:21]
Reactant: [C-]#N
Reactant: CCCCCC(O)CCCCCCCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCC(O)CCCCCCCCCCCC#N
Temperature: 90 °C
Yield: 91.8 %

Procedure:
To 17-bromoheptadecan-6-ol (1.0 g, 2.98 mmol) in dry DMF, was added NaCN (175 mg, 3.58 mmol) and the resulting reaction mixture heated at 90° C. for 16 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 ml), the organic layer was washed with cold water (3×20 ml), brine solution, dried over MgSO4 and concentrated. The crude product was purified over a silica gel column (10% EtOAc in hexane) to give 13-hydroxyoctadecanenitrile as a colorless liquid (0.77 g, 92%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH2:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH3:7]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([NH:4][S:8]([CH2:5][CH2:6][CH3:7])(=[O:10])=[O:9])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NC1CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of cyclopropylamine (1.2 ml, 17.5 mmol) in 100 ml CH2Cl2 and DMAP (2.4 g, 17.5 mmol) was added dropwise a solution of propane-1-sulfonyl chloride (2.3 ml, 19.2 mmol) in 50 ml CH2Cl2. The resulting mixture was stirred at room temperature over night and diluted with 50 ml of CH2Cl2. The mixture was extracted subsequently with water, 1 M HCl, and brine, tried over Na2SO4, filtered and the solvent evaporated to obtain 2.8 g of product (oil) which was used in the next step without further purification.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]C1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: c1ccc2c(c1)CCCN2c1cc2ccccc2[nH]1
Reactant: c1ccc2c(c1)CCCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: c1ccc2nc(-c3cc4ccccc4[nH]3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The indolyl-tetrahydroquinoline was made according to the established lanthanide triflate catalyzed Kobayashi chemistry (for a leading reference, see Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis, 1995, 1195-1202). The tetrahydroquinoline (50.0 mg, 0.102 mmol) was dissolved in 10 mL anhydrous dichloromethane and the solution was cooled to 0° C. under nitrogen atmosphere. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (47.6 mg, 0.210 mmol) in 2 mL dichloromethane was then added in a drop-wise fashion. The reaction mixture was stirred at 0° C. for additional 30 minutes. The reaction crude was filtered through celite and the solvent was evaporated in vacuo to supply a yellow solid. Further purification by flash column chromatography (alumina basic, CH2Cl2/MeOH=20:1) yielded 27.5 mg of indolyl-quinoline 517.
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:39]([S:43](Cl)(=[O:45])=[O:44])[CH2:40][CH2:41][CH3:42]>>[CH2:39]([S:43]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[S:13][C:12]([NH:11][C:9](=[O:10])[N:8]([CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16][CH:15]=2)[CH2:19][CH2:20]1)(=[O:45])=[O:44])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCS(=O)(=O)Cl
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 60.2 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (30 mg, 0.06 mmol), DIEA (32 μL, 0.18 mmol) and butane-1-sulfonyl chloride (16 μL, 0.12 mmol) to afford 19 mg (61%) of the desired product after purification.
Reaction SMILES: [O:1]=[C:2]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[CH2:3][CH2:4][C:5]([OH:7])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.N1NC(CCC(O)=O)=C2C=1CCCC2.ClC1C=CC(C2CCNCC2)=CC=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]3=[O:14])[CH2:24][CH2:23]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCC(=O)C1CCCCC1=O
Agent: Clc1ccc(C2CCNCC2)cc1
Agent: O=C(O)CCc1[nH]nc2c1CCCC2
Product: O=C1CCCCC1C(=O)CCC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 102.8 %

Procedure:
4-Oxo-4-(2-oxocyclohexyl)-n-butyric acid (4.0 g) and 1-(4-fluorophenyl)piperazine (3.6 g) were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Example 102 and 4-(4-chlorophenyl)piperidine, 7.4 g of 4-(4-fluorophenyl)-1-(4-oxo-4-(2-oxocyclohexyl)butyryl)piperazine was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:39][CH3:40]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:39][CH3:40])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OC)c3ccccc3c2OC)cc1

Procedure:
(a) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 2-chloromethyl-1,4-dimethoxy-naphthalene [J.Org.Chem. (1983),48(19),3265-3268) there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a pale yellow solid; MS: 534 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]2[C:5]([O:7][C:8](=O)[CH:3]12)=[O:6].[CH3:11][NH:12][NH2:13]>C(O)C>[CH3:11][N:12]1[NH:13][C:5](=[O:6])[CH:4]2[CH:3]([C:2]2([CH3:10])[CH3:1])[C:8]1=[O:7]
Reactant: CC1(C)C2C(=O)OC(=O)C21
Reactant: CNN
Solvent: CCO
Product: CN1NC(=O)C2C(C1=O)C2(C)C
Yield: 27.4 %

Procedure:
In 5 ml of ethyl alcohol were added 949 mg (6.77 mmol) of 3,3-dimethyl-1,2-cyclopropanedicarboxylic acid anhydride and 0.36 ml (6.77 mmol) of methylhydrazine, and the mixture was heated under reflux for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography. Recrystallization from ethyl acetate/hexane afforded 312 mg (27.3%) of the titled compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].CCN(C(C)C)C(C)C.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[O:12]=[C:3]1[CH:2]([NH:1][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2ccccc2NC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccccc2CC1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a suspension of 3-amino-3,4-dihydro-1H-quinolin-2-one (177.6 mg, 0.59 mmol) (prepared according to the procedures by Davis, A. L.; et al, Arch. Biochem. Biophys., 102, 48 (1963)) in CH3CN (5 mL) was added DIPEA (0.24 mL, 1.44 mmol), followed by addition of benzene sulfonylchloride (0.09 mL, 0.71 mmol). The mixture was stirred at RT for 1.5 h, then concentrated in vacuo. The residue was taken into EtOAc (30 mL), washed with water, brine, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (50-90%) in hexane to give the title compound (140 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:25]=[C:24]([Br:26])[CH:23]=[C:22]([N+:27]([O-])=O)[C:21]=2[S:30][C:31](=[O:35])N(C)C)[C:11]1=[O:36])[CH2:7][CH2:8][CH3:9])[CH3:2].C(O)C.[Sn](Cl)(Cl)(Cl)Cl>C(OC(=O)C)C>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:21]3[S:30][C:31](=[O:35])[NH:27][C:22]=3[CH:23]=[C:24]([Br:26])[CH:25]=2)[C:11]1=[O:36])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc([N+](=O)[O-])c2SC(=O)N(C)C)c2ccccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3[nH]c(=O)sc23)c2ccccc21
Temperature: 75 °C
Yield: 57.9 %

Procedure:
(S)-3-[3-(5-Bromo -2-dimethylcarbamoylsulfanyl-3-nitro-benzyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (70 mg, 0.11 mmol) is suspended in ethylacetate (0.5 mL)/ethanol (0.5 mL) and then tin chloride (133 mg, 0.6 mmol) is added. The resulting suspension is equipped with a reflux condenser and heated to 75° C. for 1 hour. Upon completion the reaction is cooled to room temperature and the solvents evaporated in vacuo. The resulting solid is taken up in ethyl acetate and the product is filtered. The solvent is evaporated in vacuo and the resulting solid is purified via prep reverse phase LC to give 33 mg (54%) of the title compound. LCMS (ESMS): m/z 519.7 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:7]1([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxyacetyl chloride (0.55 mL, 6.0 mmol) was added to a solution of 4-cyclopropylaniline (800 mg, 6.0 mmol) and DIEA (1.05 mL, 6.0 mmol) in DCM, and the reaction was stirred at r.t. for 2 h. The reaction was washed with brine, dried (MgSO4), and concentrated to give crude N-(4-cyclopropylphenyl)-2-methoxyacetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: N#CNc1ccccc1-c1ccccc1F
Reactant: OC1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: N=C(Nc1ccccc1-c1ccccc1F)N1CCC(O)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.5 g) and 4-hydroxypiperidine (1.4 g) in ethanol (30 ml) was heated at reflux on a steam bath for 2 hours gave a yellow foamy solid which was reacted with fumaric acid (1.3 g) in methanol (10 ml) to give N-(2'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine fumarate as a colourless solid (m.p. 214°-215° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([NH2:15])=[N:11][NH:12]2)=[CH:8][CH:7]=1>N1C=CC=CC=1>[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([NH:15][C:1](=[O:3])[CH3:2])=[N:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 3 °C
Reaction time: 48 h

Procedure:
0.32 cm3 of predistilled acetyl chloride is added to 750 mg of 6-chloro-1H-indazole-3-amine in 10 cm3 of pyridine, after the reaction medium has been cooled to about 3° C. The medium is then allowed to return to 19° C. over 48 hours. The reaction medium is evaporated to dryness under reduced pressure (2 kPa; 40° C.). The residue is taken up in 75 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is washed again with 50 cm3 of distilled water and then dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 45° C.), 700 mg of N-(6-chloro-1H-indazol-3-yl)-acetamide, melting at 240° C., are obtained.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].CO[SiH](OC)OC.[CH2:12]([O:14][SiH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH3:13]>[Ru]>[Cl:4][CH2:1][CH2:2][CH2:3][Si:15]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13]
Reactant: C=CCCl
Reactant: CCO[SiH](OCC)OCC
Agent: [Ru]
Agent: CO[SiH](OC)OC
Product: CCO[Si](CCCCl)(OCC)OCC
Yield: 41 %

Procedure:
Ruthenium has been reported to be a very efficient catalyst for the hydrosilation reaction of allyl chloride and trimethoxysilane. Japanese Patent No. 2,976,011 discloses the Ru-catalyzed hydrosilation reaction of triethoxysilane and allyl chloride to give chloropropyltriethoxysilane in about 41% yield. U.S. Pat. No. 5,559,264 describes the hydrosilation reaction of a methoxysilane and allyl chloride in the presence of a ruthenium catalyst and preferably in the substantial absence of solvent to provide a chloroalkylalkoxysilane. Tanaka et al., J. Mol. Catal. 1993, 81, 207-214 report the ruthenium carbonyl-catalyzed hydrosilation reaction of trimethoxysilane and allyl chloride and Japanese Patent Application No. 8[1996]-261232 describes the activation of ruthenium carbonyl for use as a hydrosilation catalyst for the same reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:36]([O:38][C:39]([C:41]1([CH3:45])[CH2:44][CH2:43][NH:42]1)=[O:40])[CH3:37]>C1COCC1.C(Cl)Cl>[CH2:36]([O:38][C:39]([C:41]1([CH3:45])[CH2:44][CH2:43][N:42]1[C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:40])[CH3:37]
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Reactant: CCOC(=O)C1(C)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of (3,5-dimethyl-phenyl)-acetic acid (1 eq.) in either DCM or THF was added HOBt (1.1 eq.), EDC.HCl (1.5 eq.). Then, 2-methyl-azetidine-2-carboxylic acid ethyl ester hydrochloride, Intermediate 13 (1 eq.) and TEA (4 eq.) were added. The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure and partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous layer was extracted three times with EtOAc. The organic layers were combined, washed with water then with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)[CH3:21]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:31])=[CH:25][CH:26]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127, 65.0 mg, 0.27 mmol) and ethyl-4-iodo benzoate (Reagent A, 68.0 mg, 0.27 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide (16.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 90 mg (90%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:29][C:30]#[N:31])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccccc2OC)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccccc2OC)c1
Yield: 70.3 %

Procedure:
(3,5-Dimethoxyphenyl)-(2-methoxyphenyl)methanone (1.22 g, 4.48 mmol), cyanomethylphosphonic acid diethyl ester (1.41 ml, 8.96 mmol) in anhydrous THF (30 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 9.00 ml, 9.00 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 30% EtOAc in hexane in about 30 min.) to give 3-(3,5-Dimethoxy-phenyl)-3-(2-methoxy-phenyl)-acrylonitrile as an off-white solid (0.93 g, 70%); mp, 82-84° C.: 1HNMR (CDCl3) 7.39-6.90 (m, 8H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.51-6.48 (m, 2H, Ar), 6.42 (d, J=2 Hz, 2H, Ar), 5.89 (s, 2H, double bond protons of the two isomers), 3.78 (s, 6H, 2OCH3), 3.75 (s, 6H, 2OCH3), 3.74 (s, 6H, 2OCH3); 13C NMR (CDCl3) δ 160.9, 160.7, 160.2, 159.9, 157.7, 140.6, 140.3, 131.6, 131.2, 130.9, 128.0, 126.2, 120.9, 120.7, 118.0, 117.6, 111.8, 107.1, 105.8, 101.9, 98.0, 97.3, 55.8, 55.6, 55.6; Anal. Calcd. For C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.08; H, 5.85; N, 4.78.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])(=[O:13])=[O:12].[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[S:11]([N:6]1[C:7]2[C:3](=[C:2]([CH:23]=[CH2:24])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1)(=[O:13])=[O:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(Br)cccc21
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1cc(C)ccc1OC
Temperature: 110 °C
Reaction time: 17 h
Yield: 588.4 %

Procedure:
4-bromo-1-[(2-methoxy-5-methylphenyl)sulfonyl]-1H-indole (518 mg, 1.36 mmol; Intermediate 6), tributyl(vinyl)stannane (0.438 mL, 1.50 mmol) and Pd(PPh3)2OAc2 (51 mg, 0.068 mmol) were mixed in dry toluene (8 mL) and stirred 17 h at 110° C. using a STEM block. The mixture was filtered and additional tributyl(vinyl)stannane (0.200 mL, 0.68 mmol) and Pd(PPh3)2OAc2 (30 mg, 0.040 mmol) were added with continuous stirring for 23 h. Same procedure was repeated once more (additional reagents) with continuous stirring 24 h gave full conversion. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM/hexane 2:3). This gave the desired product (2.62 g, 59%) as an off white solid. MS (ESI+) for C18H17NO3S m/z 328 (M+H)+.