Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C[C:4]1[CH:5]=[CH:6][C:7]2[O:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][C:8]=2[CH:17]=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19]>Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9][C:8]3[CH:17]=[C:4]([CH2:19][C:18]([OH:21])=[O:20])[CH:5]=[CH:6][C:7]=3[O:16][C:11]=12
Reactant: N#CCc1ccc2c(c1)Cc1cccnc1O2
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccc2c(c1)Cc1cccnc1O2

Procedure:
A solution of 11.5 g of 7-cyanomethyl-5H-[1]benzopyrano[2,3-b]-pyridine in a mixture of 60 ml of acetic acid and 25 ml of concentrated hydrochloric acid is heated under reflux for 24 hours. After concentration, water is added to the residue, and further 10% sodium hydroxide solution is added to dissolve the residue. An insoluble material is removed by extraction with chloroform. The aqueous layer is made acid with acetic acid, and the resulting crystalline precipitate is filtered off. The crystals are recrystallized from dioxane to give 8.5 g of 5H-[1]benzopyrano[2,3-b]-pyridin-7-yl-acetic acid as white needles melting at 218°C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ncnc2ccc(N3CCCC3)cc12
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2cc(N3CCCC3)ccc2n1
Yield: 84 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-6-(1-pyrrolidinyl)quinazoline was reacted with 5-aminoindole to give 4-(5-indolylamino)-6-(1-pyrrolidinyl)quinazoline in 84% yield;
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:17][O:18][CH2:19][CH2:20]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:17][O:18][CH2:19][CH2:20][O:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COCCO
Reactant: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCCOC1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 60 %

Procedure:
A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (0.50 g, 2.13 mmol) in benzene (20 ml), 2-methoxyethanol (10 ml) and p-toluensulfonic acid (20 mg) was refluxed with water separation for 20 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.48 g of the crude product, which was recrystallized from ethanol to yield 0.35 g (60%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 3.22 (s, 3H), 3.27-3.51 (m, 4H), 5.24 (s, 1H), 7.18 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.5 (d, 1H), 2.06 (s, 1H), 12.29 (s, 1H).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([C:9]2[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)c1csc(C2CCCC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc(C2CCCC2)n1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.67 g) was added to solution of ethyl 2-cyclopentylthiazole-4-carboxylate [Carboxylic Acid 2, step c] (0.9 g) in a mixture of THF (40 mL) and water (10 mL). The resulting mixture was stirred overnight. The reaction was acidified with aqueous HCl (2M, 10 mL) and the solvent evaporated. The residue was partitioned between brine (50 mL) and ethyl acetate (50 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the titled compound as a pale yellow solid. Yield 0.77 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:10]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1>C([O-])(=O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][C:9]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c(CCCN3CCCC3)cc3c(N)ncnn23)CC1
Agent: O=[Pt]=O
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(c2c(CCCN3CCCC3)cc3c(N)ncnn23)CC1
Reaction time: 6 h
Yield: 100.1 %

Procedure:
In a pressure reactor (50 mL), a mixture of the compound (132 mg, 0.31 mmol) prepared in Example 17 and platinum (IV) oxide in acetyl hydroxide (10 mL) was stirred under hydrogen atmosphere (3 atm). At 6 hours, the mixture was filtered through celite, eluting with acetyl hydroxide. The solvent was removed in vacuo. The resulting material extracted with DCM/sodium bicarbonate aqueous solution. The organic layers were dried over sodium sulfate, filtered and the solvent removed in vacuum to obtain the title compound (133 mg) having the following physical data.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=2)[C:16]([NH:18][CH:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:20])=[O:17])[CH2:10][CH2:9]1.C(NCC)C.[Cl:37][C:38]1[N:43]=[C:42](Cl)[CH:41]=[CH:40][N:39]=1.O>CC#N>[Cl:37][C:38]1[N:43]=[C:42]([N:24]2[CH2:25][CH2:26][CH:21]([CH:19]([NH:18][C:16](=[O:17])[C:15]3[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:13]([O:12][CH2:11][CH:8]4[CH2:10][CH2:9]4)[CH:14]=3)[CH3:20])[CH2:22][CH2:23]2)[CH:41]=[CH:40][N:39]=1
Reactant: COc1cc(OCC2CC2)cc(C(=O)NC(C)C2CCNCC2)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC#N
Solvent: CCNCC
Solvent: O
Product: COc1cc(OCC2CC2)cc(C(=O)NC(C)C2CCN(c3ccnc(Cl)n3)CC2)c1
Yield: 45 %

Procedure:
A solution of 3-(cyclopropylmethoxy)-5-methoxy-N-(1-(piperidin-4-yl)ethyl)benzamide 2,2,2-trifluoroacetate (Example 36, step ii, 2.0 g), diethyl amine (3 ml) and 2,4-dichloro-pyrimidine (550 mg) in CH3CN (80 ml) was stirred at room temperature for 30 minutes. 30 mL H2O was added and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by using normal phase chromatography eluting with petroleum ether containing 15% ethyl acetate to give N-(1-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)ethyl)-3-(cyclopropylmethoxy)-5-methoxybenzamide (740 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>Br>[OH:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(-c3ccncc3)oc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1cccc2cc(-c3ccncc3)oc12
Temperature: 25 °C

Procedure:
A mixutre of 4-(7-methoxy-2-benzofuranyl)pyridine (5.0 g) and 48% HBr (50 ml) was stirred at 120° C. for 1 hour. The mixture was cooled to room temperature, neutralized with 10% NaOH and 5% Na2CO3 and extracted with ethyl acetate. The organic extract was washed with brine and concentrated to give 4-(7-hydroxy-2-benzofuranyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[CH3:25][C:26](=O)[CH2:27][C:28](=O)[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:25])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: CCOCCn1cnc2c(Nc3ccc(Cl)cc3)nc(-n3nc(C)cc3C)nc21

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-[9-(2-ethoxy-ethyl)-2-hydrazino-9H-purin-6-yl]-amine and 2,4-pentanedione.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:22][C:17]1[CH:16]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: Fc1ccc(Br)cc1Cl
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(F)c(Cl)c2)C1=O
Yield: 85 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 4-bromo-2-chloro-1-fluoro-benzene (102 mL, 0.8465 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in DCM) afforded 220 mg of the product (84. 2% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:15]#[C:16]Br>>[CH2:13]([N:6]([CH2:5][C@H:2]1[CH2:3][O:4][C:16]([NH2:15])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: N#CBr
Reactant: CCN(C[C@H](N)CO)c1ccccc1
Product: CCN(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol was reacted with cyanogen bromide to give (S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine. Off-white solid. MS (ISP): 220.4 ([M+H]+)
Reaction SMILES: Cl[C:2](=[CH2:17])[CH2:3][C:4]1[C:13]2[O:12][C@@H:11]([CH2:14][OH:15])[CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:17][C:2]1[O:16][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH:11]([CH2:14][OH:15])[O:12][C:13]=3[C:4]=2[CH:3]=1
Reactant: C=C(Cl)Cc1c(O)ccc2c1O[C@@H](CO)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c3c(ccc2o1)OCC(CO)O3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.40 g (1.6 mmole) of (3S)-5-(2-chloro-2-propenyl)-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-ol in 70 mL of trifluoroacetic acid was stirred at room temperature for 26 hours. The solvent was then removed in vacuum and replaced with 100 mL of methanol. Potassium carbonate (3.0 g, 2.2 mmole) was added and the mixture stirred for an additional 1.5 hours at room temperature. The mixture was then filtered and the filtrate concentrated to a brown residue in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 0.20 g (60%) of the (S)-enantiomer of the title compound as a yellow oil. 1H-NMR (d6-DMSO): doublet 6.94 δ (1H); doublet 6.71 δ (1H); singlet 6.48 δ (1H); triplet 5.07 δ (1H); doublet of doublets 4.30 δ (1H); multiplet 4.22 δ (1H); multiplet 4.00 δ (1H); multiplet 3.65 δ (2H); singlet 2.38 δ (3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([CH3:19])=[CH:17][S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[C:18]([CH3:19])=[CH:17][S:16][C:14]=2[N:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Product: Cc1csc2nc(Cl)nc(NCc3ccccc3)c12

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[C:13](Cl)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:13](=[O:14])[C:12]1[C:11]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:19][CH:18]=[CH:17][C:16]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNC
Reactant: O=C(Cl)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Solvent: c1ccncc1
Product: CN(C)C(=O)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To 18 parts of pyridine which has been saturated with dry gaseous dimethylamine is added dropwise 1 part of 2,6-diphenoxybenzoyl chloride in 2 parts of pyridine. The resulting mixture is stirred for 30 minutes, concentrated under reduced pressure, and poured into 54 parts of water. The mixture is made acidic with concentrated hydrochloric acid, and the solid precipitate is collected, washed with water, dried, and recrystallized first from acetonitrile and then from 1-chlorobutane to give N,N dimethyl-2,6-diphenoxybenzamide, M.P. 109°-111°.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:57][N:58]([CH3:66])[CH2:59][C@@H:60]1[CH2:65][CH2:64][CH2:63][NH:62][CH2:61]1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([N:62]1[CH2:63][CH2:64][CH2:65][C@@H:60]([CH2:59][N:58]([CH3:66])[CH3:57])[CH2:61]1)=[O:25])[CH3:21])([CH3:14])([CH3:15])[CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: CN(C)C[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C[C@@H]1CCCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
At 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (870 mg, 4.54 mmol) was added to a solution (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (1.27 g, 4.54 mmol) and 1-hydroxy-7-azabenzotriazole (617 mg, 4.54 mmol) in dichloromethane (20 ml) and N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of the crude dihydrochloride salt of N,N-dimethyl-N-(((3R)-piperidin-3-yl)methyl)amine (976 mg, 4.54 mmol) in dichloromethane (20 ml) and N,N-dimethylformamide (10 ml) and ethyldiisopropylamine (3.9 ml, 22.7 mmol) were added successively. The reaction mixture was stirred for 3 days, while it was warming up to room temperature. Ethyl acetate (300 ml) was added. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate (300 ml). The aqueous phase was extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.69 g of N-[(1R)-1-benzyl-2-((3S)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](O)([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C:10]([CH2:18][OH:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C1COCC1.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:18][O:19][S:27]([CH3:30])(=[O:29])=[O:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(COS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-5-hydroxy-3-(hydroxymethyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (28.5 g, 0.1 mol) and 15 g of triethylamine were introduced as initial charge in 150 ml of THF and the solution was cooled to 5° C. (11.4 g, 0.1 mol) of mesyl chloride were added at 0-5° C. within 20 min and the mixture was after-stirred at 0° C. for 2 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated by evaporation. The viscous residue (product weight 31 g) contained, according to LC/MS, 98% of the product.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35]C)=[O:34])=[CH:28][CH:27]=2)=[N:6][N:7]([C:9]2([CH2:22][C:23]#[N:24])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)(=[O:3])[NH2:2].[Li+].[OH-].Cl>C1COCC1.O>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:9]([N:7]2[CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[C:5]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)=[N:6]2)([CH2:22][C:23]#[N:24])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)Cc1ccc(Nc2nn(C3(CC#N)CCN(C(=O)OC(C)(C)C)CC3)cc2C(N)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(CC(=O)O)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(4-carbamoyl-3-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Example 12-2) (0.10 g, 0.20 mmol) in THF (1.0 mL) was added a solution of LiOH (19 mg, 0.81 mmol) in water (0.8 mL). The mixture was stirred at ambient temperature for 2 hours. The mixture was then neutralized with 1N aqueous HCl to pH 3-4, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/EtOAc) to afford the title compound, Example #18.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[C@H:13](OS(C)(=O)=O)[C@@H:12]2[C@H:10]1[C@H:11]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:50]1[CH:54]=[N:53][C:52]([SH:55])=[N:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[C@@H:13]([S:55][C:52]2[N:53]=[CH:54][NH:50][N:51]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(SC[C@@H]2[C@H](OS(C)(=O)=O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Reactant: Sc1nc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(SC[C@@H]2[C@@H](Sc3nc[nH]n3)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Temperature: 40 °C
Reaction time: 72 h
Yield: 16.4 %

Procedure:
Di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-3-[(4-fluoro-3-methyl-phenyl)sulfanylmethyl]-4-methylsulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (5.3 g, 8.21 mmol) is dissolved in dimethylformamide (100 mL). To this mixture is added cesium carbonate (5.40 g, 16.41 mmol), 1H-1,2,4-triazole-3-thiol (3.42 g, 32.83 mmol), and sodium triacetoxyborohydride (906 mg, 4.10 mmol). The mixture is stirred at 40° C. for 72 hours. The reaction is cooled and quenched with water and aqueous NH4Cl. The mixture is transferred to a separatory funnel and extracted with diethyl ether, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (0 to 50% ethyl acetate/hexanes) to give the title compound (0.88 g, 1.35 mmol, 16.5% yield). MS (m/z): 651 (M+H).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH3:3].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH:19][CH3:20]>CN(C=O)C>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)/[CH:18]=[CH:19]/[CH3:20]
Reactant: CC=CCBr
Reactant: CCCNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/CN(CCC)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Cbz Protection A solution of propylamine (9.0 g, 152.4 mmol) and triethylamine (15.4 g, 152.4 mmol) in methylene chloride (350 mL) was cooled to 0° C. and treated with benzyl chloroformate (20.0 g, 117.2 mmol). Upon stirring at 0° C. for 1 hour the reaction was warmed to ambient temperature and quenched with 1N HCl. The reaction was partitioned between 1N HCl and methylene chloride. The organics were washed with 1N HCl, water and brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give benzyl propylcarbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 5.10 (s, 2H), 4.77 (bs, 1H), 3.16 (q, J=6.5 Hz, 2H), 1.52 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). Step B: Alkylation A solution of benzyl propylcarbamate (20.8 g, 107.9 mmol) in DMF (200 mL) was cooled to 0° C. and treated with sodium hydride (4.6 g, 194.2 mmol). The reaction was stirred to 0° C. for 15 minutes and subsequently treated with crotyl bromide (17.5 g, 129.5 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with ammonium chloride solution and partitioned between water and ether. The organics were washed with water (4×) and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (silica, 0-10% EtOAc/hexanes) gave benzyl (2E)-but-2-enyl(propyl)carbamate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.57 (bt, 1H), 5.42 (bs, 1H), 5.13 (s, 2H), 3.82 (bm, 2H), 3.19 (bs, 2H), 1.68 (bs, 3H), 1.54 (bs, 2H), 0.87 (bs, 3H). Step C: Cyclopropanation A solution of benzyl (2E)-but-2-enyl(propyl)carbamate (5.0 g, 20.2 mmol) in methylene chloride (120 mL) was cooled to 0° C. and treated with diethylzinc (12.48 g, 101 mmol) followed by diiodomethane (54.1 g, 202 mmol). The reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between methylene chloride and saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Flash chromatography (10% EtOAc/hexanes) gave 5.16 g (96%) of benzyl (2-methylcyclopropyl)methyl(propyl)carbamate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 5.13 (s, 2H), 3.16 (bm, 4H), 1.59 (bm, 2H), 1.01 (bs, 3H), 0.88 (bs, 3H), 0.68 (bs, 2H), 0.34 (bd, 1H), 0.22 (bs, 2H). Step D: Hydrogenation