Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C)C)(=O)CCC[CH2:5][C:6](C)([CH3:8])[CH3:7].[C:15](#[N:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:17][C:16]([CH3:19])([CH2:18][C:6]([CH3:8])([CH3:7])[CH3:5])[C:15]#[N:20]
Reactant: CC(C)OC(=O)CCCCC(C)(C)C
Reactant: CC(C)(C)C#N
Product: CC(C)(C)CC(C)(C)C#N

Procedure:
isopropyl neononanoate; pivalonitrile; methyl 2,2,4,4-tetramethyl pentanoate (methyl neononanoate) and methyl-3,5,5-trimethyl hexanoate.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.O.[CH2:7]([CH:9]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][NH:11][CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:8]>>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][N:11]([CH2:1][CH:3]1[CH2:4][O:5]1)[CH2:10][CH:9]([CH2:7][CH3:8])[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:19]
Reactant: ClCC1CO1
Reactant: CCCCC(CC)CNCC(CC)CCCC
Solvent: O
Product: CCCCC(CC)CN(CC(CC)CCCC)CC1CO1
Temperature: 25 °C

Procedure:
A mixture of epichlorohydrin (111 g, 1.2 mol), and water (0.27 g, 0.015 mol) was vigorously stirred at room temperature. Bis(2-ethylhexyl)amine (241.4 g, 1.0 mol) was added slowly by an addition funnel. The mixture was slowly heated to 70° C. and then stirred at 70° C. for 6 hours. The mixture was washed with aqueous potassium carbonate, K2CO3, (20%, 200 ml). Sodium hydroxide, NaOH, (36%, 200 ml) was added to the oil phase and the mixture was stirred at 70-90° C. for 18 hours. The phases were separated and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried over magnesium sulfate, MgSO4, and the solvent removed by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: CC[C@@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a solution of 60 mg of (S)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester in N,N-dimethylformamide (2.0 mL) is added 66 mg of 3-bromomethyl-4,6-dimethyl-1,2-benzoisothiazole and 36 mg potassium carbonate at room temperature. The mixture is heated to 60° C. for 2.5 h. Then 50 mL of water is added and the product is extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel to give 80 mg (82%) of (S)-3-[1-(4,6-dimethyl-benzo[d]isothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=O)[C:21]([O:26][CH2:27][O:28][CH3:29])=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH3:34][NH2:35].B.[Na]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][NH:35][CH3:34])[C:21]([O:26][CH2:27][O:28][CH3:29])=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CN
Reactant: CCOc1ccc(-c2nc(-c3cc(C=O)c(OCOC)c(C(=O)OC)c3)cs2)cc1OCC
Agent: B
Agent: [Na]
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CNC)c(OCOC)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In 30 ml of methanol was dissolved 500 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole. Thereto was added 3 ml of a 30% methylamine solution. The mixture was stirred at room temperature for 14 hours and at 70° C. for 1 hour. Thereto was added 530 ml of sodium boron hydride with stirring under ice-cooling. The mixture was stirred at room temperature for 3 hours. The solvent was removed from the reaction mixture by distillation. The residue was mixed with 40 ml of ethyl acetate and 20 ml of water, and phase separation was conducted. The organic layer was washed with 10 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was subjected to silica gel chromatography (eluent: dichloromethane/methanol=49/1 by v/v). From the eluate was obtained 150 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylaminomethylphenyl)thiazole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].[NH3:11]>CO>[NH2:11][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cncc(CCl)c1
Reactant: N
Solvent: CO
Product: N#Cc1cncc(CN)c1
Temperature: 80 °C

Procedure:
Dissolve 5-chloromethyl-nicotinonitrile (4.9 mg, 0.032 mmol) in 2.0M NH3 in MeOH (1 mL). Transfer this solution to a pressure tube. Heat the reaction solution at 80° C. for 2 h. Rotary evaporate the reaction solution (40° C.) to yield 5.1 mg of crude 5-aminomethyl-nicotinonitrile as a yellow oil. MS (m/e): 134.00 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Reaction time: 8 h
Yield: 73.3 %

Procedure:
At room temperature, to a solution of 5-(methyloxy)-1H-indole (12 g, 81.5 mmol, 1.0 eq) in acetic acid (150 mL) was added sodium cyanoborohydride (10.25 g, 163 mmol, 2.0 eq) in small portions, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give 5-(methyloxy)-2,3-dihydro-1H-indole (8.91 g, 45% yield) 1H NMR (CDCl3, 300 MHz) δ 6.76 (s, 1H), 6.60 (s, 2H), 3.54 (t, 2H), 3.01 (t, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH:13]([Cl:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Cl)(Cl)Cl>[Cl:16][CH2:13][CH2:14][CH2:15][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CCC(Cl)Br
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCCCCl)cc1

Procedure:
A mixture of 4-acetamidophenol, 182.2 g (1.2 mole), bromochloropropane, 157.4 g (1.0 mole), and potassium carbonate, 145.0 g (1.05 mole) was heated at reflux overnight in 700 ml of acetone. The acetone solution was refrigerated overnight and white crystals formed. This white solid was filtered and washed with acetone. The filtrate was stripped to dryness and the residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave an oil. The white solid was also dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave a white solid. The white solid and oil were combined and placed in acetone in the refrigerator; white crystals were obtained. The white crystals were recrystallized twice from acetone. A 5 g-sample of the white crystals was recrystallized from acetone. This furnished 1.76 g (after drying in vacuo overnight at 80° C. (23%) of white, crystalline product; m.p. 125°-127° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccncc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccncc23)CC1

Procedure:
(28.5 mg, 86%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (20 mg, 0.094 mmol), benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)[CH3:18])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(N)c1ccc(O)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CC(Nc1nc(Cl)ncc1F)c1ccc(O)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-(4-hydroxyphenyl)ethylamine to provide (±)-2-chloro-5-fluoro-N4-[1-(4-hydroxyphenyl)ethyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 7.88 (d, 1H, J=2.3 Hz), 7.50-7.47 (dd, 2H, J=1.7 and 8.7 Hz), 7.26-7.23 (dd, J=8.7 and 1.7 Hz), 5.35-5.28 (m, 2H), 1.59 (d, 3H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl-].[Cl-].[O:20]=[S:21]1(=[O:32])[CH2:25][CH2:24][CH:23]([NH+:26]2[CH2:31][CH2:30][NH2+:29][CH2:28][CH2:27]2)[CH2:22]1.Cl>C(O)CCC>[O:32]=[S:21]1(=[O:20])[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:28][CH2:27]2)[CH2:22]1
Reactant: O=S1(=O)CCC([NH+]2CC[NH2+]CC2)C1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl
Agent: [Cl-]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C3CCS(=O)(=O)C3)CC2)ncn1

Procedure:
7-2 (0.23 g, 1.79 mmol), DIEA (0.69 g, 5.37 mmol) and 1-(1,1-dioxidotetrahydrothien-3-yl)piperazinediium dichloride (the bis HCl salt of 39-1) (0.49 g, 1.79 mmol) were stirred at 150° C. in n-butanol for 18 hours overnight. Upon cooling, the solid was filtered off and washed with n-butanol and ethyl ether to afford 39-2. Hi-Res MS: calc: 298.1132 found: 298.1357. 1H-NMR (CD3OD): 7.97(s, 1H); 5.72(s, 1H); 3.55(t, 4H); 3.27(complex, 2H); 3.07(complex, 2H); 2.77(complex, 1H); 2.67(m, 2H); 2.59(m, 2H); 2.47(m, 1H); 2.12(m, 1H).
Reaction SMILES: O.[CH3:2][N:3]([CH3:35])[CH2:4][CH2:5][N:6]([CH3:34])[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]2[N:22]=[C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)=[C:9]([O:32][CH3:33])[CH:8]=1.[NH4+].[Cl-]>[Fe].C(O)C>[CH3:35][N:3]([CH3:2])[CH2:4][CH2:5][N:6]([CH3:34])[C:7]1[C:12]([NH2:13])=[CH:11][C:10]([NH:16][C:17]2[N:22]=[C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)=[C:9]([O:32][CH3:33])[CH:8]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Yield: 95.8 %

Procedure:
Water (4 mL) was added in one portion to a mixture of N′-(2-dimethylaminoethyl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine (Intermediate 169, 270 mg, 0.59 mmol), iron (196 mg, 3.51 mmol), NH4Cl (21.9 mg, 0.41 mmol) and ethanol (24 mL). The resulting mixture was heated at 105° C. for 3 h then filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and then part-purified by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo to give the title compound (244 mg, 97%) as a brown solid which was used without further purification; 1H NMR: 2.18 (6H, s), 2.37 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 3.76 (3H, s), 6.77 (1H, s), 7.03-7.26 (3H, m), 7.46 (1H, d), 7.52 (1H, s), 7.74 (1H, s), 8.18-8.35 (2H, m), 8.42 (1H, d), 11.72 (1H, s); m/z: ES+ MH+ 432.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][C:14]2[C:10](=[CH:11][NH:12][N:13]=2)[CH2:9]1)(C)(C)C.O1CCOCC1>Cl>[C:23]([C:19]1[CH:18]=[C:17]([C:8]2([NH2:7])[CH2:16][CH2:15][C:14]3[C:10](=[CH:11][NH:12][N:13]=3)[CH2:9]2)[CH:22]=[CH:21][CH:20]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCc2n[nH]cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(C2(N)CCc3n[nH]cc3C2)c1

Procedure:
[5-(3-tert-Butyl-phenyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-carbamic acid tert-butyl ester (84 mg, 0.23 mmol) was dissolved in 4 N hydrogen chloride in dioxane (2 mL, 8 mmol) at room temperatrure for 90 min, whereupon the reaction was deemed complete by TLC. The reaction mixture was concentrated under reduced pressure and the amine hydrochloride salt was basified by partitioning between 1 N aqueous NaOH and 33% isopropanol in chloroform. The organic layer was separated and the aqueous layer extracted twice with additional 33% IPA/CHCl3. The combined organic layers were dried (Na2SO4), filtered and concentrated. LC/MS analysis showed 90% pure material, which was taken to subsequent reactions: Rf=0.098 in 25% MeOH/CH2Cl2; retention time=0.98 min, method [7]; mass spec (ESI) 270 (6), 254 (23), 253 (100), 197 (12).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[F:10][P-:11]([F:16])([F:15])([F:14])([F:13])[F:12].[CH2:17]([O+](CC)CC)[CH3:18]>ClCCCl>[F:10][P-:11]([F:16])([F:15])([F:14])([F:13])[F:12].[CH2:1]([N+:5]1[CH:9]=[CH:8][N:7]([CH2:17][CH3:18])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC[O+](CC)CC
Reactant: CCCCn1ccnc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Product: CCCC[n+]1ccn(CC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.1 ml of N-butylimidazole was introduced into a 50 ml glass flask under an argon atmosphere. 2.08 g of triethyloxonium hexafluorophosphate in solution in 5 ml of 1,2-dichloroethane was then introduced. The mixture was stirred for 4 hours at room temperature. The solvent was evaporated off under vacuum using a vane pump. A colorless liquid was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cncn2)nc1
Reaction time: 0.5 h

Procedure:
2-fluoro-5-nitropyridine (0.5 g, 3.38 mmol), 1,2,4-triazole (0.22 g, 3.22 mmol) were added in DMF (6.4 mL), then cesium carbonate (3.14 g, 9.65 mmol) was added. The reaction was run at room temperature for 30 minutes. Water (50 mL) was added and product fell out of the solution. The solution was filtered and the solid was rinsed with ethyl acetate/water (1:1, 20 mL×2), hot hexane (20 mL) to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:38][N:39](C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:38][NH:39][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)[N:9]=2)[CH2:26][CH2:27]1)=[O:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General procedure to EXAMPLES 37 and 38: A DMF solution (2 mL) of acid trans-4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (100 mg, 0.23 mmol) and methylamine hydrochloride (153 mg, 2.26 mmol) in a sealed tube was charged with DIEA (394 μL, 2.26 mmol), 0.6 M HOAt in DMF (377 μL, 0.23 mmol), and then EDC (65 mg, 0.34 mmol). The reaction mixture stirred at rt for 16 h. The reaction mixture was concentrated to solids, taken up in CH2Cl2, charged with silica, and concentrated to brown solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 20 g/70 mL cartridge, eluting with 2% ˜7 N NH3 in MeOH/CH2Cl2 to 5% ˜7 N NH3 in MeOH/CH2Cl2] to afford trans-4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide as an off-white solid (60 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[FH:14].Cl>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([F:14])=[O:5]
Reactant: F
Reactant: O=C(Cl)c1cc(F)c(Cl)c(Cl)c1Cl
Agent: Cl
Product: O=C(F)c1cc(F)c(Cl)c(Cl)c1Cl

Procedure:
480 g (1.83 mols) of 2,3,4-trichloro-5-fluorobenzoyl chloride are introduced, with 240 g (12 mols) of hydrogen fluoride, at -5° to 0° C. into a stirred autoclave fitted with a pressure-control valve, the apparatus is pressure-sealed and warmed to 70° C. in steps, corresponding to the evolution of HCl. The hydrogen chloride produced is continuously released at 4-5 bar. When the evolution of HCl is complete, the mixture is cooled, the excess pressure is released and the reaction mixture is fractionated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22].[NH:31]1[CH:35]=[N:34][N:33]=[N:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:29][CH2:28][CH:27]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C@@H:14]([CH3:15])[CH2:13][CH2:12][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22]
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(O)CC2)cc1F
Reactant: c1nnn[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(N2CCC(n3cnnn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
To a solution of 1-[3-fluoro-4-[[(3S)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2 yl]methyl]phenyl]piperidin-4-ol Stereoisomer A (200 mg, 0.46 mmol, prepared as described in Example 5), tetrazole (36 mg, 0.51 mmol) and triphenylphosphine (135 mg, 0.51 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (103 mg, 0.51 mmol) dropwise and the reaction was stirred at r.t. for 16 hours. The reaction was partitioned between water and dichloromethane and the organic layer was concentrated and purified by preparative HPLC to give (3S)-2-[[2-fluoro-4-[4-(tetrazol-1-yl)-1-piperidyl]phenyl]methyl]-3-methyl-6-phenyl-thiazinane 1,1-dioxide Stereoisomer A (57.4 mg, 0.12 mmol, 26% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.99-8.96 (s, 1H), 7.49-7.43 (m, 2H), 7.43-7.29 (m, 4H), 6.89-6.82 (m, 1H), 6.82-6.75 (m, 1H), 5.18-5.07 (m, 1H), 4.50-4.36 (m, 2H), 4.33-4.25 (m, 1H), 4.16-4.03 (m, 1H), 3.87-3.76 (m, 2H), 3.10-2.98 (m, 2H), 2.47-2.37 (m, 1H), 2.31-2.23 (m, 2H), 2.19-2.04 (m, 3H), 1.89-1.73 (m, 1H), 1.70-1.59 (m, 1H), 1.13-1.06 (d, J=6.8 Hz, 3H); LCMS [M+1]+=485.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH2:11]([O:13][C:14]1[C:15](=O)[C:16](=[O:21])[C:17]=1[O:18]CC)[CH3:12]>C(#N)C.C(OCC)(=O)C>[O:18]=[C:17]1[C:16](=[O:21])[C:15]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])=[C:14]1[O:13][CH2:11][CH3:12]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Cc1cc(C#N)ccc1N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2ccc(C#N)cc2C)c(=O)c1=O
Reaction time: 48 h
Yield: 23.9 %

Procedure:
4-Amino-3-methylbenzonitrile (1.94 g, 14.7 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.53 g, 14.9 mmol) in acetonitrile (5 mL). After refluxing the mixture for 24 h a second portion of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.15 g, 6.76 mmol) was added and heating was continued for an additional 48 h. The reaction mixture was diluted with ethyl acetate (50 mL), stirred vigorously and filtered free of undissolved solid. The filtrate was chromatographed (CH3OH/CH2Cl2) to afford 0.90 g (24%) of product as a yellow solid: 1H NMR (DMSO-d6): δ 10.50 (s, 1H), 7.76-7.63 (m, 2H), 7.31 (d, 1H), 4.71 (q, 2H), 2.33 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([NH:24][C:25](=[O:26])[C:20]=12)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][C:19]3[CH:29]=[CH:28][CH:27]=[C:21]4[C:22]([NH:24][C:25](=[O:26])[C:20]=34)=[O:23])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCN3CCC(c4ccc(F)cc4)CC3)cccc21
Temperature: 97.5 °C

Procedure:
A mixture of 4-(4-fluorophenyl)piperidine hydrochloride (5.08 g, 23.2 mmol), 3-bromopropylphthalimide (6.22 g, 23.2 mmol), and potassium carbonate (15 g) in DMF (100 mL) was stirred and heated at 95-100° C. for 12 h. About 80% of the solvent was evaporated at reduced pressure, the residue was diluted with ethyl acetate (200 mL) and washed with brine (3×100 mL) and dried (Na2SO4). Solvent was evaporated and the residue was purified by column chromatography on silica gel using 1/1 hexane-ethyl acetate to 100% ethyl acetate as eluent. This product was crystallized from isopropanol to give a white crystalline solid; m.p. 80-81° C. This material was used in the next step. Concentration of the mother liquor and cooling gave the second crop.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1

Procedure:
Compound 7 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol and methyl 3-(4-hydroxyphenyl)propanoate by following the procedure described in Scheme 5
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C:15]1[C:26]([CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:25][C:18]([C:19]([O:21][CH2:22][CH2:23][OH:24])=[O:20])=[CH:17][C:16]=1[Br:33]>>[NH2:14][C:15]1[C:26]([CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:25][C:18]([C:19]([O:21][CH2:22][CH2:23][O:24][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[O:20])=[CH:17][C:16]=1[Br:33]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCN(CC)Cc1cc(C(=O)OCCO)cc(Br)c1N
Product: CCN(CC)Cc1cc(C(=O)OCCOC(=O)c2ccccc2OC(C)=O)cc(Br)c1N

Procedure:
This compound was prepared from 2-acetoxybenzoyl chloride and 1-[4-amino-3-bromo-5-diethylaminomethyl-benzoyloxy]-2-hydroxy-ethane analogous to Example 5. Oil.