Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20](Cl)=[O:21]>C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([F:26])=[C:17]([F:16])[CH:18]=2)=[CH:3][N:4]=1
Reactant: Nc1cnc(Cl)nc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cnc(Cl)nc1)c1ccc(F)c(F)c1
Yield: 61.8 %

Procedure:
A solution of 450 g (3.49 mol) of 5-amino-2-chloropyrimidine and 790 g (6.98 mol) of triethylamine in anhydrous THF was cooled to less than 5° C. in an ice bath. To this solution was added 3,4-difluorobenzoyl chloride at a rate (2 h) that maintained the temperature of the reaction mixture below 10° C. Once the addition was complete the reaction was monitored for full conversion of the starting material to product by HPLC. Following confirmation of complete conversion, the reaction mixture was concentrated under reduced pressure. The viscous residue was dissolved in ethyl acetate (4 L) and washed with water (4 L) and 2M HCl (4 L). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in ethanol (4 L) and 250 g of charcoal was added. The mixture was heated to reflux for 10 minutes and filtered through a bed of Celite® and the filtrate was concentrated under reduced pressure. The solids were recrystallized twice from acetonitrile (1 L) to yield 580 g (61.8%) of the desired product as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]4[CH2:34][CH2:33]4)=[N:30][N:29]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:19]=[C:18]3[N:29]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[N:30]=[C:31]([CH:32]4[CH2:33][CH2:34]4)[C:17]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Yield: 82.5 %

Procedure:
To a solution of 790 mg of 4-[3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester in 6 ml of dry THF 11.5 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 0.5 h. The reaction was quenched by the addition of 7 ml of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptanes/ethyl acetate) yielding 635 mg (82%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 11.8 g. of p-aminobenzonitrile and 16.2 g. of p-n-butylbenzaldehyde in 200 ml. of benzene is treated with 300 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After the addition of 3 g. of solid potassium carbonate, the mixture is filtered and evaporated, whereby there are obtained 27.0 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-butylbenzyliden)amino]benzonitrile which is obtained has a melting point of 38.1°-38.7° C. and a clearing point of 62.6° C. UV (ethanol): ε280 = 24900 (shoulder at 314 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:22])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-thiophenesulfonamide 1.9 g, 10 mmole) in 10 ml of acetone was added aqueous sodium hydroxide (10 ml of 1N. 10 mmole) followed by a solution of 4-chlorophenyl isocyanate (1.54 g, 10 mmole) dissolved in 10 ml of acetone. This mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and acidified with aqueous hydrochloric acid (10 ml of 1N, 10 mmole). The precipitate was filtered and the residue washed with hexanes and water. The solid was dried in a vacuum oven.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[CH3:11][S:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:14])=[O:13]
Reactant: COc1cccc(CO)c1
Reactant: CS(=O)(=O)Cl
Product: COc1cccc(COS(C)(=O)=O)c1

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (292 mg, 93%) from 3-methoxybenzyl alcohol (200 mg, 1.45 mmol) and methanesulfonyl chloride (249 mg, 2.17 mmol). 1H NMR (CDCl3, 300 MHz) δ2.92 (s, 3H), 3.83 (s, 3H), 5.22 (s, 2H), 6.90-7.03 (m, 3H), 7.32 (t, 1H, J=7.7 Hz) ppm.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH:13]([SH:17])[CH:14]([SH:16])[CH3:15].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>C1CCCCC1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]1[S:17][CH:13]([CH3:12])[CH:14]([CH3:15])[S:16]1
Reactant: CC(S)C(C)S
Reactant: O=Cc1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC1SC(c2ccco2)SC1C
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Into a 100 ml reaction flask equipped with magnetic stirring bar, thermometer and reflux condenser and hot plate with magnetic stirring apparatus is placed 0.5 grams para-toluenesulfonic acid, 5 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. Over a period of 35 minutes, 4.8 grams (0.05 moles) of 2-furaldehyde is added to the reaction mass with stirring. The reaction mass is then heated to reflux and refluxed for a period of 7.5 hours with stirring while removing water to reaction. After the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated sodium chloride soution and dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled using a Microvigreux column yielding the following fractions:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([CH2:13][O:20][C:21]2[CH:26]=[CH:25][C:24]3[NH:27][C:2]4[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]=4[C:23]=3[CH:22]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: CCO
Product: CCOC(=O)N1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 0 °C
Yield: 63.3 %

Procedure:
A mixture of ethyl 4-oxo-1-piperidinecarboxylate (0.23 mol) and 4-(benzyloxy)-phenyl hydrazine (0.23 mol) in ethanol (400 ml) was stirred and refluxed for 5 hours. The reaction mixture was stirred overnight at room temperature. The solid was filtered off and washed on filter with H2O/2-propanol (200 ml). The precipitate was dissolved in CHCl3 (300 ml), washed with water (2×50 ml), dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN (300 ml) and cooled to 0° C. The resulting precipitate was filtered off and dried, yielding 51.0 g (63%) of ethyl 1,3,4,5-tetrahydro-8-(phenylmethoxy)-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:26]3[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=3)[C:21]([OH:23])=[O:22])[CH:17]=1)=[CH:5]2
Reactant: O=C(O)c1cccc(N=C=S)c1
Reactant: COc1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1N
Product: COc1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1NC(=S)Nc1cccc(C(=O)O)c1

Procedure:
3-{3-[5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-phenyl]-thioureido}-benzoic acid was prepared from the product of Example 18, Step D, 5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-phenylamine (0.64 g, 1.72 mmol) and 3-carboxyphenyl isothiocyanate (0.359 g, 2.0 mmol) to give the product as a reddish-tan solid (0.104 g), mp 216-218° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][OH:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][C@H:5]([CH2:8][CH3:9])[CH2:6][O:7][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](CO)Cc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](COS(C)(=O)=O)Cc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
A flask was charged with 7.2 g (36 mmol) of (S)-2-(2,4-difluoro-benzyl)-butan-1-ol and 30 mL of dichloromethane, and the solution was cooled to 0° C. To this solution was added 7.53 mL (54 mmol) of triethylamine, and the mixture was stirred cold for 5 minutes. Then 3.1 mL (39.6 mmol) of methane sulfonyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The dichloromethane was removed under reduced pressure, and the residue was partitioned between 1 N HCl aq. and diethyl ether. The ether layer was collected and washed with sat. aq. sodium bicarbonate, water, and brine. The ether layer was dried over sodium sulfate, filtered, and the ether was removed under reduced pressure. This procedure gave 9.54 g (95% yield) of (2S)-methanesulfonic acid 2-(2,4-difluoro-benzyl)-butyl ester as an orange oil. This material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:14]1([NH:17][C:18](=[O:35])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:20]=2)[CH2:16][CH2:15]1>>[CH:14]1([NH:17][C:18]([C:19]2[CH:24]=[C:23]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:4][CH:3]=3)[C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:35])[CH2:15][CH2:16]1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)no1

Procedure:
Example 7 was prepared using 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.[BH4-].[Na+].C[OH:23]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:5]([CH:4]([OH:23])[CH3:3])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: CO
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cncn1Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the ester from Example 1, step C, (1.50 g, 5.88 mmol), in methanol (20 ml) at 0° C., was added sodium borohydride (1.0 g, 26.3 mmol) portionwise over 5 minutes. The reaction was stirred at 0° C. for 1 hr and then at room temperature for an additional 1 hr. The reaction was quenched by the addition of sat. NH4Cl solution and the methanol was evaporated in vacuo. The residue was partitioned between EtOAc and sat NaHCO3 solution and the organic extracts dried (MgSO4), and evaporated in vacuo. The residue was purified by chromatography (SiO2, 4 to 10% methanol in methylene chloride, gradient elution) to afford the title compound as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[F:24])=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[Cl:23][C:19]1[C:18]([F:24])=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:14]([C@@H:9]1[CH2:10][C@@H:11]([F:13])[CH2:12][NH:8]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@@H](F)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (7.94 g, 21.18 mmol) in CH2Cl2 (70.5 mL) was added TFA (16.32 mL, 212 mmol) and the solution was stirred at RT for 16 h. The crude reaction mixture was concentrated under vacuum and the material this obtained was used without further purification in the next step. MS (LC/MS): 274.9 [M+H]+; tR (HPLC conditions b): 2.13 min.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccc(O)c2ccccc12
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Under nitrogen, 4-methoxy-1-naphthoic acid (4.33 g) in dichloromethane (45 ml) was added boron tribromide (1M in dichloromethane, 63 ml) dropwise at 0° C., and the mixture was stirred at the same temperature for 2 hours. The resulting mixture was poured into ice-cold water and the precipitate was collected by filtration. The filter cake was added to the mixture of water and ethyl acetate, and then adjusted to pH 9 with 1N sodium hydroxide. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford 4-hydroxy-1-naphthoic acid (2.19 g) as a colorless powder.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13](/[CH:16]=[N:17]/[S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:12]=2)=[CH:7][CH:6]=1>C(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C@@H:16]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH3:1])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cc(-c2ccc(Cl)cc2)on1
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cc(-c2ccc(Cl)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A solution of methylmagnesium bromide (3.0 M in diethyl ether, 12.8 mL, 38.4 mmol, 4 equiv) was added to a solution of (R,E)-N-((5-(4-chlorophenyl)isoxazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.98 g, 9.6 mmol) in DCM (96 mL) at 0° C. The solution became orange, then faded to yellow. The reaction was stirred at 0° C. for 30 min and then carefully quenched with saturated aqueous ammonium chloride (100 mL). The layers were separated and the aqueous layer was extracted with DCM (40 mL). The combined organic layers were washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)—N—((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.0 g, white solid) in 32% yield. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 6.50 (s, 1H), 4.75 (m, 1H), 3.47 (m, 1H), 1.70 (d, J=6.8 Hz, 3H), 1.25 (s, 9H). MS m/z 327.0 (M+H)+; Rt-0.94 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:5]=1[CH2:6][NH2:7].[N-:14]([C:17]#[N:18])[C:15]#[N:16].[Na+]>>[C:15]([NH:14][C:17]([NH:7][CH2:6][C:5]1[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH3:2])=[NH:18])#[N:16]
Reactant: N#C[N-]C#N
Reactant: COc1cccc(OC)c1CN
Agent: Cl
Agent: [Na+]
Product: COc1cccc(OC)c1CNC(=N)NC#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
15 ml 2N hydrochloric acid were added to 5.0 g (29.9 mmol) 2,6-dimethoxybenzylamine and the aqueous phase was subsequently removed under vacuum. The residue was then dissolved in 50 ml 1-butanol and 2.66 g (29.9 mmol) of sodium dicyanamide were added. The reaction mixture was heated for 5.5 hours at reflux and stirred for 12 hours at room temperature. The precipitate formed was filtered off, was washed with diethylether; 6.81 g.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>[Cu]Cl.CN(C)C=O>[NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1cc[nH]n1
Reactant: Brc1cccnc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccn(-c2cccnc2)n1

Procedure:
In a typical reaction, copper(I) chloride, 3-aminopyrazole, potassium carbonate and N,N-dimethylformamide are introduced into a reaction vessel under a nitrogen atmosphere and 3-bromopyridine is gradually added. The mixture is heated at about 110° C. until most of the 3-bromopyridine has reacted. The mixture is allowed to cool and most of the solvent is removed under reduced pressure. The crude 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) is conveniently isolated and purified by crystallization from water.
Reaction SMILES: C[Mg]Br.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12].Cl.[C:15](=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH3:15])([CH3:12])[OH:13]
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccccc1N
Agent: C[Mg]Br
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccccc1N
Temperature: 25 °C

Procedure:
To a 0° C. solution of methylmagnesium bromide (45 mL of a 1.4M solution in toluene, 63 mmol) under nitrogen atmosphere was added a solution of ortho-aminoacetophenone (2.9 g, 21.5 mmol) in THF (20 mL). The mixture was warmed to ambient temperature for 45 min, cooled to 0° C., and poured into ice-water. The mixture was acidified with 6N HCl, adjusted to ca. pH 6 with saturated sodium bicarbonate solution, and then extracted with ether (2×100 mL). The combined ether fractions were dried (MgSO4), filtered and the solvent was removed under reduced pressure to give the oily product, 2-aminophenyldimethyl carbinol.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH3:31]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:30]([CH3:31])[CH3:29])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: CNC
Product: CN(C)Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and dimethylamine, the title compound was obtained as a colorless oil after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:37][C:34]1[CH:35]=[CH:36][N:31]=[N:32][CH:33]=1)=[O:9]
Reactant: Nc1ccnnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) in THF (10 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 4-pyridazinamine (may be prepared as described in Description 11; 61.9 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate (3×50 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo. The residue was washed with methanol to yield the title compound as a white solid. 95 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C(O)C>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccncc1
Yield: 43 %

Procedure:
To a solution of 3-(4-pyridyl)-acrylic acid (25.0 g, 168 mmol) in 1:1 ethanol:THF (250 mL) was added 10% Pd(0)/C (2.50 g). The reaction vessel was placed under 110 psi of H2 until 1.0 equivalent of H2 had been consumed as indicated by a pressure drop in the reaction vessel. The mixture was then diluted with 1 L of hot methanol and filtered through celite, rinsing with hot methanol. The liquid obtained was concentrated in vacuo, affording 11.0 g (43% of 3-(4-pyridyl)-propionic acid. This material was dissolved in DMF (300 mL), and to this solution was added the aminochromanol intermediate from Example 1, Step L (12.0 g, 72.5 mmol), HOBT (11.7 g, 87.0 mmol), di-iso-propylethylamine (27.8 mL, 159 mmol) and HBTU (27.5 g, 72.5 mmol). After 2 hours at ambient temperature, the reaction was quenched with 0.5 N aqueous NaHCO3 (500 mL) and diluted with ethyl acetate (1 L). The organic layer was washed with 0.5 N NaHCO3 (300 mL×3), brine (300 mL), dried (MgSO4), and concentrated in vacuo, affording 13.2 g (61%) of the amide as a white solid. A portion of this material (2.27 g, 7.61 mmol) was dissolved in dichloromethane (100 mL), and 2-methoxypropene (3.64 mL, 38 mmol) was added, followed by camphorsulfonic acid (1.20 g, 5.17 mmol). After 3 hours at ambient temperature the reaction was quenched by the addition of 1.4 mL of triethylamine, and concentrated in vacuo. Purification by flash chromatography (3% methanol in ethyl acetate) afforded the title compound as a clear oil. 1H NMR (CDCl3, 400 MHz) 8.55 (d, 2H), 7.58 (s, 1H), 7.26 (m, 3H), 7.00 (d, 1H), 6.84 (t, 1H), 5.81 (s, 1h), 4.88 (s, 1H), 4.40 (d, 2H), 4.18 (m, 3H), 3.02 (m, 3H), 2.70 (m, 1H), 1.62 (s, 3H), 1.30 (s, 1H).
Reaction SMILES: N(OC(C)(C)C)=O.[Br-:8].C(OC([N:16]1[CH2:22][CH2:21][C:20]2[S:23][C:24](N)=[N:25][C:19]=2[CH2:18][CH2:17]1)=O)(C)(C)C>C(#N)C>[Br:8][C:24]1[S:23][C:20]2[CH2:21][CH2:22][NH:16][CH2:17][CH2:18][C:19]=2[N:25]=1
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2CC1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Brc1nc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
238 μl tert.-butyl nitrite was added to 447 mg cupper (II) bromide in 50 mL acetonitrile. The reaction was stirred 10 min. at RT and then 270 mg 2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]-azepine-6-carboxylic acid tert-butyl ester was added. The reaction was stirred 30 min. at 60° C. The reaction was purified by HPLC. The residue was dissolved in 10 mL dichlormethane and 10 mL trifluor acetic acid and stirred at RT for 1 h. The mixture was evaporated to give 112 mg of the desired product. Rt: 0.92 min (method I), (M+H)+: 233/235