Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN[C@@H](C)C1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1C[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-[(3S*,5S*)-5-methylpyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f66) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:25])([CH3:24])[O:6][CH2:7][C@@H:8]([N:11]1[C:16](=[O:17])[CH:15]=[N:14][C:13]2[CH:18]=[CH:19][C:20]([O:22]C)=[N:21][C:12]1=2)[CH2:9]O)([CH3:4])[CH3:3].CCN(CC)CC.CS(OS(C)(=O)=O)(=O)=O>C(Cl)(Cl)Cl.O>[CH3:3][C:2]([Si:5]([CH3:24])([CH3:25])[O:6][CH2:7][C@H:8]1[N:11]2[C:12]3[N:21]([C:20](=[O:22])[CH:19]=[CH:18][C:13]=3[N:14]=[CH:15][C:16]2=[O:17])[CH2:9]1)([CH3:1])[CH3:4]
Reactant: COc1ccc2ncc(=O)n([C@@H](CO)CO[Si](C)(C)C(C)(C)C)c2n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1Cn2c(=O)ccc3ncc(=O)n1c32
Yield: 88.2 %

Procedure:
To a solution of 4-[(1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-(hydroxymethyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (1 g, 2.74 mmol) in CHCl3 (50 mL) was added Et3N (0.953 mL, 6.84 mmol) followed by a solution of methanesulfonic anhydride (0.953 g, 5.47 mmol) in CHCl3 (50 mL). The reaction mixture was stirred at reflux temperature for 5 h. The crude of reaction was diluted with water, washed with NaCl, dried (MgSO4), filtered, and concentrated. Purification by flash chromatography using a 40 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded (2S)-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (0.806 g, 88%) as a tan solid.
Reaction SMILES: [NH:1]([N:8]1[C:20](=[O:21])[C:19]2[C:18](=[O:22])[C:17]3[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>CS(O)(=O)=O>[OH:26][C:9]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[CH:16][C:17]=3[C:18](=[O:22])[C:19]=2[C:20](=[O:21])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: O=C1c2[nH]c3ccc([N+](=O)[O-])cc3c(=O)c2C(=O)N1Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2cc([N+](=O)[O-])ccc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
2-Anilino-7-nitro-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (0.830 g, 2.37 mH) was dissolved with stirring in methanesulfonic acid (42 mL) to give a deep orange solution. Methanol (420 mL) was added and the resulting yellow solution heated to reflux for 2 hours to give a yellow suspension. Heat was removed and the suspension was stirred at room temperature for 3 hours. The solids were removed by filtration, and the filtrate was allowed to stand for 20 hours. More solids formed in the filtrate during this time, and the suspension was refiltered. This filtrate was then concentrated to about 250 mL and diluted with water (400 mL) to give a yellow precipitate. These solids were collected and washed with aqueous methanol (50%) and then ether to give the title compound (0.590 g, 71%) as a yellow powder, mp 382-385° C.; MS(CI): 351 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]#[C:14][NH2:15].[Na]>>[CH2:1]([O:8][CH2:9][CH:10]1[O:11][C:14]([NH2:15])=[N:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: c1ccc(COCC2CO2)cc1
Agent: [Na]
Product: NC1=NCC(COCc2ccccc2)O1

Procedure:
The title compound was prepared from 2-benzyloxymethyl-oxirane and sodium hydrogen cyanamide according to the procedures employed for the preparation of the compound in Step 2 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)[CH:18]=3)[NH:13][N:12]=2)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:29])[N:3]=1.CCN(C(C)C)C(C)C.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>O1CCOCC1.CCOC(C)=O>[Cl:29][C:4]1[N:3]=[C:2]([NH:45][CH:42]2[CH2:43][CH2:44][O:39][CH2:40][CH2:41]2)[C:7]([C:8]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][C:21]4[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=4)[CH:18]=3)[NH:13][N:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: NC1CCOCC1
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(Cl)nc1NC1CCOCC1

Procedure:
A solution of 2,6-dichloro-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]pyridine-3-carboxamide (80 mg, 0.18 mmol) in dioxane (1 mL) was heated at 100° C. for 24 hours in the presence of DIPEA (0.1 mL, 0.55 mmol) and tetrahydro-2H-pyran-4-amine. (28 mg, 0.28 mmol) Reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography on silica gel using DCM/EtOH 95:5 as the eluant, affording 57 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccnc1CNCc1ncccc1C
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester and DIPEA in CH3CN gave 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH:65]([Si:68]([CH:73]([CH3:75])[CH3:74])([CH:70]([CH3:72])[CH3:71])[SH:69])([CH3:67])[CH3:66]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:69][Si:68]([CH:70]([CH3:72])[CH3:71])([CH:73]([CH3:75])[CH3:74])[CH:65]([CH3:66])[CH3:67])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCc1cc(F)ccc1Br)C(=O)OC(C)(C)C
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)[Si](Sc1ccc(F)cc1CCN(C)C(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 160 °C

Procedure:
[2-(2-Bromo-5-fluoro-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (3.0 g, 9.03 mmol), tris(dibenzylideneacetone)dipalladium (0) (83 mg, 0.09 mmol), bis(2-diphenylphosphinophenyl)ether (97 mg, 0.18 mmol), sodium tert-butoxide (1.10 g, 11.7 mmol), triisopropylsilanethiol (1.90 g, 9.93 mmol) and dry toluene (15 mL) are all placed in an Emrys Optimizer EXP 20 mL microwave reactor tube. The reaction vessel is sealed and subjected to microwave heating at 160° C. for 15 minutes. Upon cooling the mixture is poured onto a plug of silica and the product is eluted with ethyl acetate-heptane (1:10). This furnishes 1.6 g (40%) of the title compound as an oil, which is used in the next step without further purification.
Reaction SMILES: C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:14][C:15](=O)[CH2:16][C:17]1([CH2:37][C:38](O)=[O:39])[S:21][C:20]2[CH:22]=[C:23]3[S:27][C:26]([CH2:32][C:33](O)=[O:34])([CH2:28][C:29](O)=[O:30])[S:25][C:24]3=[CH:36][C:19]=2[S:18]1)C.C(O)C>O>[OH:34][CH2:33][CH2:32][C:26]1([CH2:28][CH2:29][OH:30])[S:25][C:24]2[CH:36]=[C:19]3[S:18][C:17]([CH2:37][CH2:38][OH:39])([CH2:16][CH2:15][OH:14])[S:21][C:20]3=[CH:22][C:23]=2[S:27]1
Reactant: CCOC(=O)CC1(CC(=O)O)Sc2cc3c(cc2S1)SC(CC(=O)O)(CC(=O)O)S3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: OCCC1(CCO)Sc2cc3c(cc2S1)SC(CCO)(CCO)S3
Temperature: 25 °C

Procedure:
A dry flask under argon atmosphere was charged with diethyl ether (2600 ml) and LiAlH4 (21.2 g 0.56 mol) Benzo[1,2-d:4,5-d']bis(1,3)dithiole-2,2,6,6-tetraacetic acid ethyl ester (80.2 g, 0.139 mol) was added and the mixture was refluxed for 26 h. The mixture was cooled to ambient temperature and ethanol (165 ml) was carefully added followed by water (410 ml). The ether was decanted off and the white precipitate was stirred with water (3300 ml) to give a slurry. After acidification with hydrochloric acid the slurry was filtered and the crude product was washed with water and dried.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[C:20]([NH2:28])(=[NH:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[C:11]1([C:10]2[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:28]=[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[N:27]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)c1ccncc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Agent: Cl
Product: O=C(O)c1cnc(-c2ccncc2)nc1-c1ccccc1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and isonicotinamidine hydrochloride, followed by saponification as described in example 3c) there was obtained 4-phenyl-2-pyridin-4-yl-pyrimidine-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:23]#[N:24]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:23]#[N:24])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C#N)cn2)CC1
Temperature: 180 °C

Procedure:
A mixture of 4-(5-bromo-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.80 mmol, 1.0 equiv), copper(I) cyanide (0.38 g, 4.20 mmol, 1.5 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.58 g, 0.56 mmol, 0.2 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.31 g, 0.56 mmol, 0.2 equiv) in DMAc (8 mL) was heated by microwave irradiation to 180° C. for 30 min. The organic phase was concentrated under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.20 g (23%) of the title compound. MS (ISP): 304.4 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C.[F:23][C:24]1[C:25]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=O)=[N:26][C:27]2[NH:28][C:29](=[O:34])[CH2:30][CH2:31][C:32]=2[CH:33]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOC(C)=O.ClC(Cl)C>ClCCCl>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:25]2[N:26]=[C:27]3[C:32]([CH2:31][CH2:30][C:29](=[O:34])[NH:28]3)=[CH:33][C:24]=2[F:23])[CH2:12][CH2:11]1
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a suspension of 1-(2,3-dichloro-phenyl)-piperazine hydrochloride (0.80 g, 3.0 mmol) in 1,2-dichloroethane (10 mL) was added triethylamine (0.61 mL, 6.0 mmol). The mixture was stirred for 30 min at room temperature and 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.76 g, 3.0 mmol) was added as a suspension in 1,2-dichloroethane (5 mL). The mixture was stirred for 30 min and NaBH(OAc)3 (0.89 g, 4.2 mmol) was added as a solid. The reaction was stirred at room temperature for 4 h. The mixture was poured into EtOAc/dichloroethane and washed with saturated NaHCO3 and brine. The organic layer was washed with aqueous citric acid (pH 4.5) and brine, dried over Na2SO4 and concentrated to a slurry. Et2O was added and the solid was collected by filtration. Purification by liquid chromatography (Biotage 40S, gradient of CH2Cl2 to 10% MeOH/CHCl3) gave the title compound as a white solid (738 mg, 1.58 mmol, 53%). MS: APCI: M+1: 467.3 (Exact Mass: 466.13).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C([Sn]([C:62]#[N:63])(CCCC)CCCC)CCC.[C-]#N.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:16]=[C:5]1[C:4]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:3]2[C:2]([C:62]#[N:63])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(C#N)cccc21
Temperature: 25 °C
Yield: 34.7 %

Procedure:
A mixture of 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.10 g, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 0.23 mmol) and 2-(di-tert-butylphosphino)biphenyl (0.07, 0.23 mmol), tributyltin cyanide (0.07 g, 0.23 mmol) and potassium cyanide (0.02 g, 0.23 mmol) was purged with nitrogen and anhydrous acetonitrile (10.0 mL) was added. The reaction mixture was refluxed for 16 h. After cooling down to ambient temperature, the reaction mixture was diluted with ethyl acetate (20.0 mL), washed with water (20.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The brown residue was subjected to column chromatography eluting with ethyl acetate/hexane (65%) to give the title compound (0.03 g, 33%) which was recrystallized from ether to get a colorless solid: mp 128-129° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.42-7.37 (m, 1H), 7.29-7.27 (m, 1H), 7.09 (d, 1H), 6.53 (s, 1H), 6.03 (s, 1H), 5.87 (dd, 2H), 4.91 (q, 2H), 3.86-3.63 (m, 2H), 1.74-1.62 (m, 2H), 1.43-1.26 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.5, 157.1, 149.5, 143.5, 142.4, 135.4, 129.7, 128.3, 126.4, 116.3, 114.8, 112.3, 108.8, 102.2, 93.7, 78.7, 58.3, 40.6, 28.9, 26.7, 22.2, 13.9; MS (ES+) m/z 377.5 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:16][NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3](NC(OCC)=O)[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]([CH2:3][NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:16][NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: [H][H]
Reactant: CCOC(=O)NCC(C)C(NC(=O)OCC)NC(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)NCC(C)CNC(=O)OCC

Procedure:
10 g of the 2-methyl-1,1,3-tri(ethoxycarbonylamino)propane obtained in stage a) are dissolved in 90 ml of ethanol, 3 g of palladium on active carbon (10% Pd) are added, and hydrogenation is carried out in a stirred autoclave at 165° C. and 100 bar of hydrogen for 15 hours. Complete conversion gives 2-methyl-1,3-di(ethoxycarbonylamino)propane with a selectivity of 96%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) in dichloromethane (1 ml) was added at room temperature triethylamine (89 mg, 123 μl, 880 μmol) and methanesulfonyl chloride (27.5 mg, 18.7 μl, 240 μmol). The mixture was allowed to stir at room temperature for 18 h, poured into ice/water (5 ml) and 1N sodium hydroxide solution (5 ml) and extracted with dichloromethane (2×15 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4) and evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as an off-white solid (43 mg, 66%), MS (ISP) m/z=409.4 [(M+H)+], mp 220° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:19][CH3:20])[C:16]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:22]#[N:21])=[CH:24][CH:25]=2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
(RS)-(4-Benzyloxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile to give (RS)-2-(4-benzyloxy-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide according to general procedure B. Colorless solid. MS 387.3 ([M+H]+)
Reaction SMILES: B.[NH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](O)=[O:11])[CH2:6][CH2:5]1.[ClH:13]>O1CCCC1>[ClH:13].[NH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NC[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 1.0 M solution of borane in tetrahydrofuran (250 mL, 260 mmol.) was added slowly dropwise to a suspension of trans-4-(aminomethyl)cyclohexanecarboxylic acid (10.0 g, 64.0 mmol.) in tetrahydrofuran (250 mL). Gas evolution was observed. The reaction mixture was heated at reflux for 14 hours. The resulting solution was cooled to 0° C. and carefully treated dropwise with 1 N methanolic hydrochloric acid (250 mL). Gas evolution was observed. The white suspension obtained was stirred for 1 hour at 23° C. and subsequently concentrated. Methanol was added to the residue and the suspension was concentrated. This procedure was repeated twice to give trans-4-(Aminomethyl)cyclohexanemethanol hydrochloride (10.6 g, 93% yield) as a white solid.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:17]2=[O:23].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH:16]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[C:17]2=[O:23]
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2c(C)cc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A suspension of 12.2 g (0.53 moles) of sodium hydride in a liter of toluene are maintained under stirring in a 2 liter flask for 2 hours at room temperature, and 85 ml (0.69 moles) of diethylcarbonate are then added. The mixture is heated to 90° C. and 25 g of 5,7-dimethyl-1-tetralone (0.14 moles) dissolved in 150 ml of toluene are added, in about 2 hours. The reaction mixture is kept under stirring for a further 8 hours at 90° C. until the reagent disappears. At the end the reaction mixture is hydrolyzed by pouring it into ice containing 50 ml of glacial acetic acid. The phases are separated and extracted repeatedly with ethyl ether, the overall organic phase is washed with water saturated with NaHCO3, then with water until neutrality and finally dried on anhydrous Na2SO4. Upon removal of the solvents at reduced pressure, 33 g of the desired pure ketoester (XXV) are obtained in the form of a red oil (96% yield). NMR spectra show that the product is present in solution in ketone and enolic form in a ratio of 55% and 45% respectively.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1([O:16][Si](C)(C)C)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:16][C:3]1([C:2]([F:22])([F:1])[F:21])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C)(C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.3 %

Procedure:
To a solution of tert-butyl 4-(trifluoromethyl)-4-(trimethylsilyloxy)piperidine-1-carboxylate (0.512 g, 1.50 mmol), in methanol (10 mL) was potassium carbonate (0.25 g, 1.81 mmol). The resulting mixture was stirred at room temperature for 12 hours. Filtration and concentration provided an orange residue that was purified by silica gel chromatography (97:3 dichloromethane:methanol) to give tert-butyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (0.07 g, 14% yield). MS (EI) for C11H18F3NO3: 269 (MH+).