Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](=[O:20])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3,4-dichlorophenyl)3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g, 0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. Piperidine (1.87 g, 0.022 mole) was added and the reaction was allowed to stir at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(Cl)c1Cl

Procedure:
A mixture of 2,3-dichlorobenzoic acid (39.4 g 0.2M) and thionyl chloride (100 ml) was heated to reflux for 21/2 hours. The cooled solution was evaporated down in vacuo and distilled under nitrogen. Yield 35.5 g (85%), b.p. 146°-148° C. at 31 mm of mercury pressure.
Reaction SMILES: [F:1][C:2]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:23]([CH:25]([C:33]#[N:34])[C:26]([CH3:32])([CH3:31])[C:27](OC)=[O:28])#[N:24].CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[NH2:24][C:23]1[C:25]2[C:26]([CH3:32])([CH3:31])[C:27](=[O:28])[NH:34][C:33]=2[N:17]=[C:15]([C:7]2[C:8]3[C:9](=[N:10][C:11]([CH3:14])=[N:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:2]=3[F:1])[N:6]=2)[N:16]=1
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3cccc(F)c3F)c2n1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1

Procedure:
400 mg (1.11 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 277 mg (1.33 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 175 mg (1.56 mmol) of potassium tert-butoxide, and the mixture was heated to reflux for 24 h. A little water was added and the reaction solution was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). The product-containing fractions were concentrated and the residue was stirred with water/isopropanol. The solids were filtered off and purified again by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 170 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [OH-].[Na+].[I-:3].[Na+].[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].O>CO>[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[I:3])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cccc(O)c1
Reactant: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
21 g (520 mmol) of sodium hydroxide and then 79 g (520 mmol) of sodium iodide are added to a solution of 69 g (500 mmol) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0° C. and then Javel water (520 mmol) is added dropwise. The reaction mixture is stirred at 0-5° C. for 2 hours and then at room temperature for 15 h. After evaporating the methanol, the reaction mixture is acidified with a concentrated solution of hydrochloric acid. The precipitate is filtered, washed with water and dried. 41.9 g of 3-hydroxy-4-iodobenzoic acid is obtained in the form of a white solid with melting point of 218° C. The aqueous phase is extracted with ethyl acetate, the organic phase obtained is dried over magnesium sulfate, filtered, and evaporated. The residue obtained is taken up in heptane and the precipitate obtained is filtered.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][N:21]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([C:38](=[O:39])[CH2:37][N:21]3[CH2:22][CH2:23][C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20]3=[O:19])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,4-diphenylpiperidine (Matrix, 0.48 mg, 2.00 mmol) in dichloromethane was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.59 g, 2.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.77 g, 4.00 mmol) and N,N-dimethylpyridin-4-amine (0.024 g, 0.20 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.25-7.37 (m, 12H), 7.14-7.24 (m, 8H), 4.20 (s, 2H), 3.61-3.67 (m, 2H), 3.50 (t, J=6.4 Hz, 2H), 3.42-3.47 (m, 2H), 2.80 (t, J=6.6 Hz, 2H), 2.35-2.41 (m, 2H), 2.26-2.31 (m, 2H); MS (DCI+) m/z 515 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.[C:37](O)(=[O:39])[CH3:38]>S(=O)(=O)(O)O>[C:37]([O:36][CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH2:27])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34])(=[O:39])[CH3:38]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 54 %

Procedure:
6.02 g (11.9 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4) was dissolved in a mixed solvent of 160 mL of acetic acid and 40 mL of concentrated sulfuric acid and the solution was stirred at 100° C. for 35 minutes. The reaction solution was cooled on ice, poured into ice water and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with a 1N aqueous solution of sodium hydroxide, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) and recrystallized from chloroform/methanol/n=hexane to give 2.43 g of Compound 123 (yield: 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: CCOC(=O)CCCCCCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCCCCCCO)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanoate (9.6 g) in tetrahydrofuran (THF) (50 ml) was added dropwise, at room temperature, to a suspension of lithium aluminum hydride (0.96 g) in tetrahydrofuran (THF) (50 ml). The mixture was stirred for 30 minutes at room temperature, to which was then added, under ice-cooling, water (6 ml). Insolubles were filtered off, then the filtrate was concentrated. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (2:3), was obtained 7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptanol, which was recrystallized from chloroform-ether to give colorless needles, m.p.78-79° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][O:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2(F)COC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2(F)COC2)c(OCC2CC2)n1
Yield: 53.6 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid (Example 134 f, 25 mg, 93.5 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 20.9 mg, 112 μmol) to give the title compound (20 mg, 54%) as colorless oil, MS (EI): m/e=400.2 [MH+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([Br:24])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CS(Cl)(=O)=O.[CH:30]([N:33](CC)C(C)C)(C)C.[C-]#N.[K+]>C(#N)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:30]#[N:33])=[C:18]([Br:24])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(CO)c(Br)c1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: N#CCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reaction time: 336 h
Yield: 46.3 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropane-carboxamide (1.08 g, 2.78 mmol), methanesulfonyl chloride (0.24 mL, 3.1 mmol), and N,N-diisopropylethylamine (0.72 mL, 4.1 mmol) were dissolved in acetonitrile (27 mL) at 25° C. After complete dissolution, KCN (450 mg, 6.95 mmol) was added and the reaction was stirred for 14 d. The reaction was diluted with dichloromethane (25 mL) and washed with water (25 mL). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclo-propane carboxamide (514 mg, 46%). ESI-MS m/z calc. 398.0, found 399.1 (M+1)+; retention time 3.24 minutes.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([O:8]CC)=O)[C:2]#[CH:3].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]=[C:20]=[S:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[C:13]=1[N:19]1[C:6](=[O:8])[CH2:5][N:4]([CH2:1][C:2]#[CH:3])[C:20]1=[S:21]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: C#CCNCC(=O)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of ethyl N-propargylaminoacetate (14.1 g), 2,6-dimethylphenylisothiocyanate (16.3 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, washed with 1N HCl (100 mL), then with water. The organic layer was separated, dried over anhydrous magnesium sulfate, then evaporated to dryness. The residual oil was triturated with hexane. The solid w, as collected by filtration. Recrystallization from hexane-EtOAc afforded the title compound (12.5 g) as yellow solid, m.p. 117°-121° C. Anal. Calcd. for. C14H14N2S2O: C, 65.09; H, 5.46; N, 10.84. Found: C, 65.23; H, 5.43; N, 10.88. Mass spectrum (EI, M.+) m/z 258.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][NH2:20].[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:20]([CH2:19][CH2:18][OH:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Temperature: 25 °C
Reaction time: 144 h

Procedure:
3-Benzyloxy-2-methyl-4-pyrone (4.8 g), prepared as described under Example 10, and 2-hydroxyethylamine (1.22 g) are dissolved in water (220 ml) and ethanol (100 ml) containing sodium hydroxide (2 g) is added. The mixture is stirred at room temperature for 6 days and is then acidified with concentrated hydrochloric acid to pH 2, and evaporated to dryness. The resulting colourless solid is washed with water and extracted into chloroform (2×50 ml). The chloroform extracts are combined, dried over magnesium sulphate, and evaporated to yield 3-benzyloxy-1-(2'-hydroxyethyl)-2-methylpyrid-4-one, as a white solid (3.4 g), m.p. 198°-199° C.
Reaction SMILES: NC[C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CC(O)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:45][N:46]([CH:48]=O)[CH3:47]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:48][N:46]([CH3:45])[CH3:47])=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CN(C)C=O
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple BOC-4-(aminomethyl)benzoic acid (48 mg) with 4-chloro-3-(pyridin-2-yl)aniline (35 mg). The crude reaction mixture was treated with TFA (1 mL) containing trace amounts of water for 1 h. The reaction mixture was concentrated to yield 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (80 mg) was dissolved in DMF (5 mL) and treated with AcOH (10 L), paraformaldehyde (48 mg), and sodium triacetoxyborohydride (125 mg) for 16 h. The reaction mixture was concentrated, and the crude residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, dried (MgSO4) and concentrated. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((dimethylamino)methyl)benzamide. MS (Q1) 365.0 (M)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5].C(N(CC)CC)C.[C:19]([O:23][C:24](ON=C(C1C=CC=CC=1)C#N)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([NH:2][CH2:3][CH:4]([N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)[CH3:5])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CC(CN)n1nnnc1S
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(CNC(=O)OC(C)(C)C)n1nnnc1S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 1-[1-(aminomethyl)ethyl-1H-tetrazole-5-thiol hydrochloride (17 g) and triethylamine (19.33 g) in 50% aqueous dioxane (80 ml) was added a solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (21.4 g) in dioxane (50 ml) under cooling in an ice bath. The mixture was stirred for 1.5 hours at ambient temperature and concentrated to third volume. The aqueous solution was washed with diethyl ether and the washings were reextracted with aqueous solution of potassium carbonate. The two aqueous solutions were combined, washed with diethyl ether and mixed with ethyl acetate. The mixture was acidified with 10% hydrochloric acid and the organic layer was separated out. The solution was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with n-hexane to give 1-[1-{(N-t-butoxycarbonylamino)methyl}ethyl]-1H-tetrazole-5-thiol (19.15 g), mp 156° to 158° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:23]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([O:8][CH:9]([C:18]([F:19])([F:21])[F:20])[CH2:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1ccccn1)C(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(CC(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c1ccccn1
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 88.5 %

Procedure:
A solution of 810 mg (2.54 mmol) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine in 8 mL of THF was treated with 2.54 mL (3.81 mmol, 1.5 eq.) of LDA (1.5 M solution in cyclohexane) at −75° C. After stirring at −75° C. for 45 minutes, 474 μL (7.61 mmol, 3.0 eq.) of methyl iodide was added at −75° C. The resulting mixture was stirred at this temperature for 10 minutes and quenched with saturated NH4Cl solution. The product was extracted into ether. The ethereal layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 750 mg (89%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluoro-1-methylbutyl]pyridine (a mixture of two diastereomers) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[C:12]([F:24])[CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:32]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:33])=[C:15]3[C:10]([CH:11]=[C:12]([F:24])[CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(NC3CCCCC3)n(-c3ccc(Cl)cc3)nc2c1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1c2ccc(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-6-fluoro-2H-indazol-3-yl]-cyclohexyl-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 5 days under reflux conditions to give the title compound as off-white solid. MS: m/e=469.4 [M+H+].
Reaction SMILES: [CH2:1]([NH:3][C:4](=S)[NH:5][NH2:6])[CH3:2].[Cl:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>Cl>[ClH:8].[CH2:1]([NH:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([CH3:17])[NH:6][N:5]=1)[CH3:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCNC(=S)NN
Agent: Cl
Product: CCNc1n[nH]c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.1 %

Procedure:
A mixture of 47.68 g (0.4 mole) of 4-ethyl-3-thiosemicarbazide and 65.8 g (0.4 mole) of ethyl 2-chloroacetoacetate was stirred under nitrogen atmosphere for 1.5 hr at ambient temperature then treated with 200 mL of 2N ethanolic hydrogen chloride. The mixture was stirred for ~72 hr, filtered to remove the amorphous sulfur, and the solvent was removed in vacuo to give a deep amber oil which solidified. Recrystallization from acetone gave 27 g of crude product which was recrystallized from benzene/petroleum ether to give 23.5 g of fine white crystals, mp 140°-148° C. Rework of the filtrate gave an additional 17.5 g of crude product.
Reaction SMILES: [F:1][C:2]1([F:27])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:29]1[O:30][C:31]([CH3:34])=[N:32][N:33]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:27][C:2]1([F:1])[CH:7]([NH:8][C:9]2[N:26]=[C:12]3[C:13]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=4[F:25])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:6][CH2:5][N:4]([C:29]2[O:30][C:31]([CH3:34])=[N:32][N:33]=2)[CH2:3]1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCNCC4(F)F)nc23)c(F)c1F
Reactant: Cc1nnc(Br)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5F)cccn4n3)C(F)(F)C2)o1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A solution of N-(3,3-difluoropiperidin-4-yl)-8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (see example 275b, 75 mg, 196 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (41.5 mg, 254 μmol) and diisopropylethylamine (50.6 mg, 68.3 μL, 391 μmol) dissolved in dry dioxane (4 mL) was stirred at 110° C. for 3 hours. Further diisopropylethylamine (50.6 mg, 68.3 μL, 391 μmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (41.5 mg, 254 μmol) were added and heated to 110° C. for 12 hours. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was as white foam (36 mg, 40%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].O.NN>[Ni].C(O)C>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:4]1[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])c(C)cn1C
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Nc2ccccc2N)c(C)cn1C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
A suspension of Raney nickel in ethanol is added to a warm solution (50° C.) of 80 g of ethyl 1,4-dimethyl-3-(2-nitrophenyl)amino-1H-pyrrole-2-carboxylate and 30 ml of hydrazine hydrate in 2 l of ethanol in such portions that a temperature of 70° C. is not exceeded. After 45 minutes nitrogen evolution is no longer observed when Raney nickel is added. The Raney nickel is filtered off hot and is washed with ethanol. After concentration of the filtrate, 58 g (82%) of the title compound of m.p. 90° C. (from isopropanol) are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])[CH2:7][CH2:8][CH3:9])[CH3:2].[C:19](C1NC=CN=1)(C1NC=CN=1)=[O:20]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:19]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)Nc1ccccc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a solution of (S)-3-(2-Amino-phenylamino)-hexanoic acid ethyl ester (650 mg, 2.6 mmol) in THF (10 mL) was added carbonyl diimidazole [CDI] (842 mg, 5.2 mmol) at room temperature under nitrogen atmosphere. The solution was stirred at the same temperature for 12 hours. The solution was concentrated and the residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (700 mg, 98%) as a colorless oil.