Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:21])[C:18]([Cl:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:21])[C:18]([Cl:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)c(Cl)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Oc1cc2c(cc1Cl)CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A mixture of N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (135 mg) and 4N hydrogen chloride in ethyl acetate (3 ml) was stirred under ice-cooling for 2 hours and at room temperature for 5 hours and evaporated in vacuo. The residue was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford N-benzyl-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine (100 mg) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(I)c1
Reactant: Clc1ccc2cc[nH]c2c1
Product: Clc1cccc(-n2ccc3ccc(Cl)cc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-chloro-3-iodobenzene: ESMS m/e: 261.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22](O)(=[O:26])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CCCC(=O)O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(C)c(-c2ccc(C(=O)NCC3CC3)cc2)c1
Reaction time: 72 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (30 mg, 0.11 mmol) and butyric acid (22.0 mg, 0.25 mmol) were mixed in THF (3 ml). Carbodiimde resin (295 mg, 0.31 mmol) was added and shaking continued for 72 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX), to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)butyramide. NMR; δH [2H6]—DMSO 9.85,(1H, s), 8.60,(1H, t), 7.91,(2H, d), 7.50-7.49,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.16,(2H, t), 2.25,(2H, t), 2.15,(3H, s), 1.59,(2H, m), 1.04,(1H, m), 0.89,(3H, t), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.14 min, MH+351.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:31]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]3[C:30]=1[N:21]=[CH:22][CH:23]=[CH:24]3)(=[O:32])=[O:33])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc3cccnc23)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.8 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 8-quinolinesulfonyl chloride (25 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (3 mg, 11%) as a white solid. MS (ESI+) for C21H21N3O3S m/z 396 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: NN
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28C (497 mg, 1 mmol) in 1,4-dioxane (10 mL) was added hydrazine hydrate (0.3 mL). After stirring at ambient temperature for about 4 hours, the mixture was concentrated. The residue was washed with hexane and dried under vacuum to give the title compound, which was used in the next step without further purification. MS: 493 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (2S)-2-amino-4-methyl-pentanamide hydrochloride (1:1) (CAN 10466-61-2) as starting materials, and isolated (46 mg, 62%) as light yellow gum; LC-MS (UV peak area, ESI) 100%, 347.2081 (M+H).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:21]([Cl:22])=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=3[Cl:23])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:15]([Cl:23])=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][C:21]=3[Cl:22])[CH:11]=2)[NH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(C=O)cc3Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(CO)cc3Cl)cc12

Procedure:
Preparation is carried out in analogy to the procedure of Example VI from 5.0 g (12.2 mmol) of aldehyde derivative from Example XVI by means of 1.39 g (36.61 mmol) of sodium borohydride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].[CH3:14]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:11][CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(S)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 3-chloro-4-nitrothiophenol (3.3 g) in N,N-dimethylformamide (5 ml) was added dropwise to an ice-cooled mixture of 60% sodium hydride (0.7 g) in N,N-dimethylformamide (10 ml). The mixture was stirred at 0° to 5° C. for 1 hour. To the above mixture was added dropwise methyl iodide (3.7 g) at 5° C. The mixture was stirred at room temperature for 1 hour, poured into ice-water (80 ml), and extracted with toluene. The extract was dried and evaporated. The oily residue was crystallized from a mixture of hexane and ethanol to give crystals of 3-chloro-4-nitrothioanisole (2.8 g).
Reaction SMILES: Br[C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C1(C(N)C2CCCCC2)CCCCC1.[CH:27]([Cl:29])=[CH2:28]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1)(C)(C)C.C1(C=CC(O)=CC=1)O.CC(N(C)C)=O>[Cl:29][CH:27]=[CH:28][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C
Reactant: C=CCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: CC(=O)N(C)C
Product: Cc1c(C=CCl)c(C(F)(F)F)nn1C
Temperature: 140 °C
Yield: 82.8 %

Procedure:
2.0 g of 4-bromo-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole together with 18.5 mg of palladium acetate, 73.2 mg of di(tert-butyl)phenylphosphine, 60.3 mg of tetrabutylammonium bromide, 10 mg of hydroquinone, 1.8 g of dicyclohexylmethylamine and 23 ml of dimethylacetamide are placed in a stainless steel autoclave. 2.6 g of vinyl chloride are condensed into this autoclave at low temperature and the autoclave is subsequently closed. It is subsequently heated at 140° C. for 20 hours. It is then cooled and depressurized and the reaction mixture is dewatered and worked up by extraction. 1.53 g (83% of theory) of 4-(2-chloroethenyl)-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole are isolated.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:5]=2[CH:4]=1)#[N:2]>C1COCC1.[Pd]>[C:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)C=Cc1ccc2sc(C#N)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc2sc(C#N)cc2c1
Yield: 57.5 %

Procedure:
Methyl 3-(2-cyanobenzo[b]thiophen-5-yl)acrylate (2.5 g) was hydrogenated in THF (20 ml) using 10% palladium on carbon (0.5 g) as catalyst until the majority of the starting material had disappeared by thin layer chromatography (silica plates eluting with ethyl acetate/hexane 1:4). The mixture was filtered and evaporated to give methyl 2-cyanobenzo[b]thiophene-5-propionate (1.45 g) contaminated with ~20% of starting material. Sodium hydroxide (0.23 g) was added to a mixture of this product (1.4 g) in THF (10 ml) and uater (3 ml) and the mixture was stirred for 2 hours. The mixture was adjusted to ~pH 5 with concentrated hydrochloric acid and concentrated by evaporation to remove the THF present.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CN2C(=O)CCc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (1S)-1-(hydroxymethyl)-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.909 g, 8.67 mmol) in DCM (100 ml) at 0° C. under argon was treated with triethylamine (1.450 ml, 10.40 mmol) and then methanesulfonyl chloride (0.743 ml, 9.54 mmol) and then allowed to warm to rt and stirred at rt for 1 h. The reaction mixture was then treated with saturated aqueous bicarbonate (100 ml) and the mixture was extracted with DCM (2×100 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude intermediate [(2S)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl methanesulfonate. This was dissolved in dry acetonitrile (100 ml) and then treated with pyridine (1.402 ml, 17.34 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and heated at 70° C. for 20 h. After 20 h more 1,1-dimethylethyl 4-piperidinylcarbamate (3.47 g, 17.34 mmol) and pyridine (1.402 ml, 17.34 mmol) were added and the temperature was increased to reflux (heating block 95° C.) and reaction was stirred at this temperature for a further 4 h. The reaction mixture was then evaporated, saturated aqueous NaHCO3 (200 ml) was then added and the mixture was extracted with DCM (3×200 ml). The combined organic solvents were then dried (MgSO4), filtered and evaporated to give the crude product as a brown solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: Cc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1cccc(-c2ccc3nnc(C)n3n2)c1

Procedure:
As in Example 36, a mixture of 6.0 g. of 3-chloro-6-(m-tolyl)pyridazine and 4.34 g of acetylhydrazine in 100 ml. of n-butanol is refluxed for 48 hr. to give 2.0 g. of cream colored crystals, m.p. 160°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2ncccc2[nH]1
Reaction time: 12 h

Procedure:
To a suspension of 3-(3-nitropyridin-2-yl)-2-oxopropionic acid ethyl ester (Preparation 30, 1.00 g, 4.20 mmol) in ethanol (30 mL, absolute) was added palladium (10% on activated carbon, 447 mg, 0.42 mmol) and the reaction mixture placed under an atmosphere of hydrogen at a pressure of 20-30 psi for 12 h with vigorous stirring. The reaction mixture was filtered through celite, washing with ethyl acetate and the filtrate concentrated in vacuo to ca. 20 mL. Water (150 mL) was added and the mixture cooled to between 0° C. and 5° C. The precipitate that formed was collected by filtration and dried to give the title compound as a beige solid. δH (CDCl3): 1.44 (3H, t), 4.45 (2H, q), 7.25 (1H, dd), 7.39 (1H, s), 7.75 (1H, dd), 8.57 (1H, dd), 8.98 (1H, s).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.C(N(CC)[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[S:25][CH3:26])C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]2[C:16](=[O:27])[CH2:26][S:25][C:18]=2[CH:19]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1SC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)SCC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexanes, 13 mL, 20.8 mmol) was added slowly to a solution of diisopropylamine (2.91 mL, 20.8 mmol) in THF at −78° C. The mixture was stirred under nitrogen for 30 min and N,N-diethyl-4-methoxy-2-(methylthio)benzamide (2.4 g, 9.47 mmol), dissolved in 10 mL of anhydrous THF was added to the reaction dropwise. Stirring was continued at −78° C. for 1 h and the cooling bath was removed. After 12 h, the reaction was cooled back down to −78° C. and a 1:1 mixture of methanol and acetic acid (10 mL) was added to the mixture. The reaction was stirred for 15 min and the cooling bath was removed and allowed to warm up to room temperature. The reaction was diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 15 to 40% ethyl acetate in hexanes to obtain an off white solid. Yield=1.4 g. MS (M−H)− 179.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6]([CH2:21][CH2:22][Cl:23])([C:7]#[N:8])[C:9]#[N:10]
Reactant: ClCCBr
Reactant: N#CC(C#N)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCCl)Cc1cccc(Cl)c1
Yield: 44.7 %

Procedure:
Using 1.01 g of (3-chlorobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 1.38 g of potassium carbonate, and 1.44 g of 1-bromo-2-chloroethane, and according to the process described in the Production Example 1, there was obtained 0.60 g of 2-(3-chlorobenzyl)-2-(2-chloroethyl)malononitrile (the present compound (63)).
Reaction SMILES: [CH:1]([C:3]1[O:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)=O.Cl.[NH2:15]O>>[C:1]([C:3]1[O:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)#[N:15]
Reactant: NO
Reactant: O=Cc1cc2[nH]c(C(=O)O)cc2o1
Agent: Cl
Product: N#Cc1cc2[nH]c(C(=O)O)cc2o1

Procedure:
2-Formyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (see, for example, Krutosikova, A.; Dandarova, M.; Alfoldi, J., Chem. Pap., 48: 268-73 (1994)) was treated with hydroxylamine hydrochloride according to Procedure G.
Reaction SMILES: O.[NH2:2][C@@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:11]([NH:2][C@@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)C[C@@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)C[C@@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
1.5 g (10 mmol) of D-asparagine hydrate in 5 ml of 2N sodium hydroxide solution were treated with 1.01 ml (10 mmol) of benzaldehyde and the reaction mixture was stirred homogeneously at room temperature for 20 minutes. Subsequently, 114 mg (3 mmol) of sodium borohydride were added portionwise, the mixture was stirred at room temperature for 30 minutes, a further 114 mg of sodium borohydride were added and, finally, the mixture was stirred at room temperature for a further 30 minutes. Thereafter, the aqueous phase was washed with methylene chloride and then adjusted to pH 6-7 with 1N hydrochloric acid, upon which crystallization occurred. The separated crystals were filtered off, washed with water and ether and finally dried in a high vacuum, to obtain 0.6 g (27%) of N-benzyl-3-carbamoyl-D-alanine as a white powder. MS 223 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[N:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:32][CH:27]([C:23]3[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=3)[CH2:28][CH2:29]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCCCn1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCn3ccc4ccccc43)CC2)c1
Yield: 83.4 %

Procedure:
Prepared as above, using 1-(5-chloropentyl)-1H-indole (22.2 mg, 0.100 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (24.6 mg, 0.100 mmol), K2CO3 (27.6 mg, 0.200 mmol), NaI (23.0 mg, 0.150 mmol) and DMF (1.00 mL), giving the desired product as a yellow oil (36 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.08-6.52 (m, 11H), 4.19 (t, 2H, J=7.2 Hz), 3.26-3.10 (m, 2H), 2.71-2.55 (m, 2H), 2.55-2.42 (m, 2H), 2.35-2.12 (m, 2H), 2.12-1.80 (m, 6H), 1.80-1.57 (m, 2H), 1.51-1.34 (m, 2H), 1.31 (d, 6H, J=6.8 Hz); ESMS m/e: 432.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CN(C=O)C.C(OCC)(=O)C.O.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.C(O)C>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=[C:2]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[N:7]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccncc2)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccncc2)nc(-c2ccc(N)cc2)n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
trans-Dichlorobis(triphenylphosphine)palladium (II) (0.039 g, 0.06 mmol) was added to a mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-4-ylsulfonylmethyl)pyrimidine (0.411 g, 1.11 mmol), 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.366 g, 1.67 mmol) and sodium carbonate (0.233 mL, 5.56 mmol) in 18% DMF in a mixture of 7:3:2 DME:water:ethanol (100 mL) at RT under nitrogen. The resulting solution was stirred at 90° C. for 5 hours. The reaction was cooled and diluted with ethyl acetate and water. The reaction mixture was extracted with ethyl acetate and the combined organics dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired material as a white solid (0.453 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:12][C:13]([Cl:17])=[CH:14][CH2:15][NH2:16]>C(OCC)C>[Cl:12][C:13]([Cl:17])=[CH:14][CH2:15][NH:16][C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NCC=C(Cl)Cl
Solvent: CCOCC
Product: O=C(NCC=C(Cl)Cl)Nc1ccc(Cl)c(Cl)c1

Procedure:
To 0.02 mol of 3,4-dichlorophenylisocyanate, dissolved in 40 ml of ethyl ether, were admixed, at room temperature, 0.02 mol of N-(3,3-dichloroallyl)-amine (prepared starting from 3,3-trichloropropene with hexamethylentetramine--see e.g., Italian patent application No. 28,867 A/76).
Reaction SMILES: C(Cl)Cl.[Si:4]([O:11][CH2:12][CH2:13][CH2:14][OH:15])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[Si:4]([O:11][CH2:12][CH2:13][CH:14]=[O:15])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69024.3 %

Procedure:
Tetrapropylammonium perruthenate (0.18 g, 5.3 mmol) was added to a mixture of methylene chloride (20 mL) and acetonitrile (2 mL) containing 3-(tert-butyldimethylsilyloxy)-propanol (2 g, 0.01 mmol), N-methylmorpholine N-oxide (1.76 g) and 4 Å molecular sieves. The reaction mixture was stirred at RT overnight and then filtered through a pad of silica gel. The filtrate was concentrated under vacuo to afford 3-(tert-butyldimethylsilyloxy)-propionaldehyde (1.3 g, 66%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:20])[C:5](=[O:19])[S:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:17]=[O:18])=[N:14]2)=[CH:9][CH:8]=1>C(O)C.C(Cl)(Cl)Cl>[CH3:3][N:4]([CH3:20])[C:5](=[O:19])[S:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH2:17][OH:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)Sc1ccc2ccc(C=O)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Sc1ccc2ccc(CO)nc2c1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
Referring now to FIG. 22, NaBH4 (6.2 mg, 0.165 mmol) was added to a solution of 18 (43.1 mg, 0.165 mmol) in ethanol (1 mL), and the resulting mixture was stirred at room temperature. After TLC indicated the reaction was complete, the solvent was evaporated and the residue obtained was dissolved in chloroform. The solution was then washed with brine (×2), dried over Na2SO4, and evaporated to provide 19 (36.5 mg, 0.139 mmol, 85% yield) was obtained and carried to the next step without further purification.