Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15](C)[CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.CC1[C:26]([C:27]([OH:29])=O)=CC=CC=1.[NH3:30]>>[NH2:30][C:2]1[C:11]2[N:12]=[C:13]([CH:27]([CH3:26])[OH:29])[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)C(C)n1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Reactant: Cc1ccccc1C(=O)O
Product: CC(C)Cn1c(C(C)O)nc2c(N)nc3ccccc3c21
Temperature: 165 °C

Procedure:
4-Chloro-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methyl benzoate (3.7 g; 0.009 mol, Example 19) was added to 15% methanolic ammonia (50 mL). The mixture was heated in a Parr bomb at 165° C. for 6 hr. The resulting reaction mixture was evaporated and the residue was slurried in aqueous sodium bicarbonate. The product was extracted into dichloromethane, and the extracts were washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The organic extracts were evaporated to dryness to yield an oily solid. The solid was purified by silica gel column chromatography to yield two products, the intended product and the 4-(N-methyl) derivative. The intended product (Rf=0.36 silica gel TLC, ethyl acetate eluent) was recrystallized from ethanol to yield a solid m.p. 190-195° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[N+]=[N-].NC(N)=O.CCOCC.[OH:21][C@H:22]1[CH2:42][C@@:41]2([CH3:43])[C@@H:33]([CH2:34][C@@H:35]([OH:45])[C@:36]2([OH:44])[C:37](=[O:40])[CH2:38][OH:39])[C@H:32]2[C@H:23]1[C@:24]1([CH3:47])[C:29]([CH2:30][CH2:31]2)=[CH:28][C:27](=[O:46])[CH:26]=[CH:25]1>CO>[C:2]([O-:7])(=[O:1])[CH3:3].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:45][C@@H:35]1[CH2:34][C@@H:33]2[C@:41]([CH3:43])([CH2:42][C@H:22]([OH:21])[C@H:23]3[C@H:32]2[CH2:31][CH2:30][C:29]2[C@:24]3([CH3:47])[CH:25]=[CH:26][C:27](=[O:46])[CH:28]=2)[C@@:36]1([OH:44])[C:37](=[O:40])[CH2:38][OH:39]
Reactant: [N-]=[N+]=CCOC1CCCCO1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Agent: NC(N)=O
Solvent: CCOCC
Solvent: CO
Product: CC(=O)[O-]
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOC1CCCCO1)[C@]2(O)C(=O)CO

Procedure:
A solution of 2-(tetrahydropyran-2-yloxy)-1-diazoethane (prepared from 69.1 g of N-]2-(tetrahydropyran-2-yloxy)ethyl]urea by the procedure described in (a) - (e) above) in 600 ml of 3:1 ether-pentane is stirred with 200 ml each of ether and methanol at 0°C. Fourteen g of 11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions. After nitrogen evolution ceases the solvents are removed in vacuo and the residue is dissolved in chloroform and chromatographed on a 150 g-silica gel column. Elution with chloroform and then 1:1 chloroformethyl acetate gives 4.0 g of TLC pure 16α-[2-(tetrahydropyran-2-yloxy)ethoxy]-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)C(C)C)(C)C.Cl.[CH3:21][NH:22][O:23][CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:22]([O:23][CH3:24])[CH3:21])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.5 %

Procedure:
A solution of 2-chloronicotinic acid (20.0 g, 127 mmol) in N,N-dimethylformamide (600 mL, 0.21M) was treated with N,N-diisopropylethylamine (66 mL, 379 mmol), N,O-dimethylhydroxylamine hydrochloride (13.63 g, 140 mmol), and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (84.25 g, 190 mmol). The reaction was stirred at 25° C. over 3 d. The resulting reaction was concentrated in vacuo, taken up in ethyl acetate (400 mL) and washed with a saturated aqueous ammonium chloride solution (2×250 mL), a saturated aqueous sodium bicarbonate solution (2×250 mL), and a saturated aqueous sodium chloride solution (250 mL). The organics were dried over magnesium sulfate, filtered and rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix IntelliFlash 280 column chromatography, 400 g silica gel column, 25-50% ethyl acetate/hexanes) afforded 2-chloro-N-methoxy-N-methyl-nicotinamide (23.58 g, 93%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:24][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:47])[CH2:35][CH2:36][C:37](ON1C(=O)CCC1=O)=[O:38]>ClCCl>[CH3:32][O:33][C:34](=[O:47])[CH2:35][CH2:36][C:37]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:7]2[NH:6][C:5]3[S:24][C:2]([CH3:1])=[CH:3][C:4]=3[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:9][C:8]=2[CH:18]=1)=[O:38]
Reactant: Cc1cc2c(s1)Nc1ccc(CN)cc1N=C2N1CCN(C)CC1
Reactant: COC(=O)CCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)NCc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(C)sc1N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepin-7-yl)methanamine, prepared as described in Example 3, (40 mg, 0.12 mmol) in dichloromethane (2 mL) was added triethylamine (0.030 mL, 0.22 mmol) and succinic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester, prepared as described in the previous step, (31 mg, 0.13 mmol). The solution was stirred at room temperature for 1 hour and concentrated. The crude was loaded onto a silica column, eluted with 3-5% methanol/dichloromethane containing ammonium hydroxide to give the title compound as a yellow solid. LC-MS: m/z 456 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH:14]([OH:42])[C:15]2[C:39]([F:40])=[CH:38][C:18]([CH2:19][O:20][CH2:21][C@@H:22]3[CH2:24][C@@H:23]3[CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:17][C:16]=2[F:41])[CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:14]([C:15]2[C:16]([F:41])=[CH:17][C:18]([CH2:19][O:20][CH2:21][C@@H:22]3[CH2:24][C@@H:23]3[CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[CH:38][C:39]=2[F:40])=[O:42])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2cc(F)c(C(O)C3CC3)c(F)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2cc(F)c(C(=O)C3CC3)c(F)c2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (0.09 mL of a 2M soln in DCM, 0.177 mmol) was dissolved in DCM (0.8 mL) at −78° C. DMSO (35 mg, 0.44 mmol) was added, and the resulting solution was stirred at −78° C. for 5 minutes. A solution of the product from step A (40 mg, 0.09 mmol) in DCM (1 mL) was added followed by Et3N (90 mg, 0.89 mmol). The reaction was warmed to room temperature, and stirred at that temperature for 15 minutes. The reaction was quenched with sat. NH4Cl(aq.), and extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (0-15% EtOAc in hexanes) which provided title compound. 1H NMR (500 MHz, CDCl3) δ 6.94 (dd, 2H), 4.58 (d, 1H), 4.49 (d, 1H), 4.18-4.00 (br m, 2H), 3.58-3.46 (m, 2H), 2.74-2.61 (m, 2H), 1.83 (d, 1H), 1.73 (d, 1H), 1.47 (s, 9H), 1.38-1.19 (m, 5H), 1.13-1.09 (m, 2H), 0.97-0.88 (m, 1H), 0.80-0.68 (m, 2H), 0.06-0.00 (m, 1H). MS (ESI) m/z 450 [M+H]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C([C:10]1C=[CH:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][CH:16]=2)[CH:11]=1)(O)=O>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[CH:10]=[CH:11][N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][CH:16]=2)[CH:13]=1)=[O:3]
Reactant: O=C(O)c1ccn(-c2cncc3ccccc23)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1ccn(-c2cncc3ccccc23)c1
Temperature: 22 °C
Reaction time: 15 h

Procedure:
0.82 mL (9.4 mmol) of oxalyl chloride is added to a solution, cooled to a temperature in the region of 5° C., of 0.75 g (3.15 mmol) of 3-carboxy-1-(isoquinol-4-yl)-1H-pyrrole in 25 mL of dichloromethane under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), resulting in 0.9 g of 3-chlorocarbonyl-1-(isoquinol-4-yl)-1H-pyrrole hydrochloride in the form of a cream-coloured solid which is used directly in the following step.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1S(N)(=O)=O)([O-])=[O:2].NCP(=O)(OC(C)C)[O:17][CH:18](C)C.[C:26]1([CH3:32])C=CC=CC=1>>[C:26]([O:17][CH3:18])(=[O:2])[CH3:32].[CH3:8][CH2:9][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)OP(=O)(CN)OC(C)C
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccccc1
Product: CCCCCC
Product: COC(C)=O

Procedure:
10 g (0.58 mole) of 2-nitrophenylsulfonamide are suspended in 20 ml of toluene and heated to reflux temperature. 17.0 g (0.087 mole) of diisopropyl aminomethylphosphonate are added dropwise to the hot solution. The reaction mixture is then boiled under reflux for 10 hours, cooled and evaporated. Chromatographing the residue over silica gel with a 4:1 methyl acetate/hexane mixture gives 1.6 g of 2-(di-i-propoxyphosphonylmethylamino)-phenylsulfonamide in the form of a yellow oil.
Reaction SMILES: O1CCOCC1.OS(O)(=O)=O.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19].[CH3:24][C:25](=[CH2:27])[CH3:26]>C(=O)=O.O>[CH3:24][C:25]([O:19][C:18](=[O:20])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:16][CH2:15][CH2:14][NH2:13])([CH3:27])[CH3:26]
Reactant: C=C(C)C
Reactant: CCCC(CCCN)C(=O)O
Agent: Cl
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CCCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
To a cooled solution of 7 mL of dioxane was added 0.7 mL of conc. H2SO4 dropwise. The solution turned purple in color. To this solution, 700 mg (3.5 mmol) of 5-amino-2-propylpentanoic acid monohydrochloride (7) was slowly added and the resulting solution was transferred into a pressure bottle. To this solution was added 12 mL of isobutylene and the resulting solution was slowly stirred magnetically under pressure at room temperature for 20 hours. The reaction vessel was cooled in dry ice, pressure was released, and the reaction vessel warmed up to room temperature to vaporize the excess isobutylene. The reaction mixture was poured into 100 mL of cold water. The aqueous part was extracted with 2×150 mL of ether, basified with 4N sodium hydroxide to pH 10, and extracted with 3×100 mL of ethyl acetate to yield 380 mg (1.76 mmol, 49%) of rac-5-amino-2-propylpentanoic acid 1,1-dimethylethyl ester (8) as an oil. NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:23](=[O:25])[CH3:24])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 103.6 %

Procedure:
(5R)-3-(3-Fluorophenyl)-5-hydroxymethyloxazolidin-2-one (40 g, 0.189 mol, see Upjohn WO 94-13649) was suspended by stirring in dry dichloromethane (400 ml) under nitrogen. Triethylamine (21 g, 0.208 mol) and 4-dimethylaminopyridine (0.6 g, 4.9 mmol) were added, followed by dropwise addition of acetic anhydride (20.3 g, 0.199 mol) over 30 minutes, and stirring continued at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate (250 ml) was added, the organic phase separated, washed with 2% sodium dihydrogen phosphate, dried (magnesium sulfate), filtered and evaporated to give the desired product (49.6 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Product: NS(=O)(=O)c1cccc(-c2ccccc2)c1
Yield: 66.4 %

Procedure:
Using preparation method 2, 3-bromobenzenesulfonamide (236 mg, 1 mmol) was reacted with phenylboronic acid (134 mg, 1.1 mmol). Purification by flash chromatography on SiO2 with CH2Cl2 gave 3-phenylbenzenesulfonamide as an off-white crystalline solid (155 mg, 66%). NMR 1H (ppm, d6-DMSO): 8.11 (s, 1H), 7.84 (d, J3=7.8 Hz, 1H), 7.70 (d, J3=7.8 Hz, 1H), 7.56-7.53 (m, 2H), 7.48 (t, J3=7.8 Hz, 1H), 7.43-7.34 (m, 3H), 5.10 (br. s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C([Li])CCC.[Cl:15][Si:16]1(Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Cl:15][Si:16]1([CH:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[C:4]2[CH3:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: Cl[Si]1(Cl)CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si]2(Cl)CCCCC2)C(C)=C1C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Into a flask containing 100 ml of tetrahydrofuran, 2,3,4,5-tetramethylcyclopenta-2,4-diene (3.67 g, 30 mmol) was added, and then n-butyl lithium (12 ml) was added in droplets thereto at 0° C. The reaction temperature was gradually increased to room temperature, and the reaction mixture was allowed to react for 8 hours. The temperature of the reaction solution was decreased to −78° C., after which the reaction solution was added with dichlorosilacyclohexane (5.07 g, 30 mmol) and then allowed to react for 12 hours. After the reaction, volatile material was removed, the resultant reaction product was extracted with 100 ml of hexane, and more volatile material was removed, thus obtaining 7.01 g of chloro-2,3,4,5-tetramethylcyclopentadienyl silacyclohexane as light yellow oil. Subsequently, the chloro-2,3,4,5-tetramethylcyclopentadienyl silacyclohexane thus obtained was dissolved in 100 ml of tetrahydrofuran, without additional purification, and 2.18 g of lithium tert-butylamide was added in droplets thereto at 0° C., after which the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction, the volatile material was removed, the resultant reaction product was extracted with 100 ml of hexane, and more volatile material was removed, thus obtaining 7.42 g of (tert-butylamido)(2,3,4,5-tetramethylcyclopenta-2,4-dienyl)silacyclohexane as light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:27](=[O:29])[CH3:28])[CH2:15]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1cnn2CC1CCCNC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCC(Cn2ncc3c([N+](=O)[O-])cccc32)C1
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of 4-nitro-1-(piperidin-3-ylmethyl)-1H-indazole (0.050 g, 0.139 mmol), triethylamine (0.097 mL, 0.699 mmol) in DCM (1 mL) was treated with acetic anhydride (0.0158 mL, 0.168 mmol) at ambient temperature and stirring continued for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate, extracted with DCM, dried (phase separator silicone treated filter paper) and concentrated to provide 1-(3-((4-nitro-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone (0.022 g, 52% yield) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5]([CH3:16])=[CH:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:8]=1.[OH2:17].NN.[CH2:20]([OH:22])[CH3:21]>>[C:3]1(=[O:17])[N:1]([CH2:2][C:3]2[NH:4][C:5]([CH3:16])=[CH:6][CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[CH:8]=2)[C:20](=[O:22])[C:21]2=[CH:16][CH:5]=[CH:6][CH:7]=[C:8]12
Reactant: O
Reactant: CC1=CC(c2cccc(Cl)c2)C=C(CN)N1
Reactant: CCO
Agent: NN
Product: CC1=CC(c2cccc(Cl)c2)C=C(CN2C(=O)c3ccccc3C2=O)N1

Procedure:
2-Aminomethyl-6-methyl-4-(3'-chlorophenyl)-1,4-dihydropyridine -3-(carboxylic acid ethyl ester)-5-carboxylic acid methyl ester ##STR8## is obtained from 0.1 mol of 2-phthalimidomethyl-6-methyl-4-(3'-chlorophenyl)-1,4-dihydropyridine-3-(carboxylic acid ethyl ester)-5-carboxylic acid methyl ester and 22 ccs of hydrazine hydrate in 500 ccs of ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:27](=[O:29])[CH3:28])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)OC(C)(C)C)c3)nc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}carbamate (1.13 g, 3.0 mmol) produced in Example C63(iv) and N,N-dimethylpyridine-4-amine (1.22 g, 10 mmol) in pyridine (10 mL) was added dropwise acetyl chloride (0.79 g, 10 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and triturated with diethyl ether to give the title compound (0.65 g, 52%) as a white amorphous.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.Cl.[F:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:31]([NH:33][CH3:34])=[O:32].CCN(C(C)C)C(C)C>C(#N)CC.CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:39][CH2:40][N:41]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:42][CH2:43]1)[C:31]([NH:33][CH3:34])=[O:32]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 33.2 %

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (129 mg, 0.553 mmol) in propiononitrile (1.2 mL) was added ((cyanomethyl)trimethylphosphonium iodide (161 mg, 0.664 mmol)) and 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (151 mg, 0.553 mmol) and DIEA (290 μl, 1.659 mmol)). The vial was heated to 90° C. for 16 hours. The crude r×n was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (83 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.33 (d, J=4.5 Hz, 1H), 7.45-7.70 (m, 3H), 6.88-7.10 (m, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.83 (dd, J=11.1, 2.5 Hz, 1H), 3.36 (s, 2H), 3.08 (br. s., 4H), 2.75 (d, J=4.5 Hz, 3H), 2.56-2.64 (m, 1H), 2.50 (br. s., 4H), 1.97-2.12 (m, 1H), 1.85 (d, J=11.1 Hz, 1H), 1.63 (d, J=11.9 Hz, 1H), 1.29-1.57 (m, 3H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:27]([O-])(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:26]=[C:15]3[C:16]([N:20]4[CH2:25][CH2:24][N:23]([C:27](=[O:29])[CH3:28])[CH2:22][CH2:21]4)=[N:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(Nc2nc3c(N4CCNCC4)nccn3n2)cc(OC)c1
Reactant: CC(=O)[O-]
Product: COc1cc(Nc2nc3c(N4CCN(C(C)=O)CC4)nccn3n2)cc(OC)c1

Procedure:
N-(3,5-dimethoxyphenyl)-8-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-2-amine (synthesized as described earlier) is converted into the acetate using standard conditions.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=N)[O:17][CH3:18])[N:11]=2)[N:9]=1)[NH2:3].Cl.C(=O)([O-])[O-:22].[K+].[K+]>O1CCCC1>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:17][CH3:18])=[O:22])[N:11]=2)[N:9]=1)[NH2:3]
Reactant: COC(=N)c1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-[6-[(imino)(methoxy)methyl]pyridin-2-yl]thiazole (0.9 g) in 50% aqueous tetrahydrofuran (60 ml) was adjusted to pH 1.0 with 6N-hydrochloric acid and stirred for 5 minutes at ambient temperature. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-methoxycarbonylpyridin-2-yl)thiazole (0.54 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH:19][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(NC(=O)c2cc(C(N)=O)ccc2OC)c(OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,4-dimethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.