Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[N:20]=[C:21](Br)[C:22]2[N:23]([CH:25]=[CH:26][N:27]=2)[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([NH:17][C:21]3[C:22]4[N:23]([CH:25]=[CH:26][N:27]=4)[CH:24]=[C:19]([Br:18])[N:20]=3)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(N)cc21
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1cnc2ccc(Nc3nc(Br)cn4ccnc34)cc21

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (3H-Benzoimidazol-5-yl)-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: [OH-].[NH4+:2].C(O)C.[CH3:6][Si:7]([CH3:22])([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:15][O:14]1>O>[NH2:2][CH2:15][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:7]([CH3:22])([CH3:6])[CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: [NH4+]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN
Temperature: 50 °C

Procedure:
Aqueous ammonium hydroxide (25%; 10 g, 150 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 50° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 50° C. for an additional 8 hours. Ethanol and water were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(N)CCC.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([N+:10]([O-:12])=[O:11])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[CH3:13]
Reactant: O=Cc1ccccc1
Reactant: Cc1c(F)cccc1CC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCCCN
Product: Cc1c(F)cccc1CC(=Cc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 81.1 %

Procedure:
The compound of step 2 (17.951 g, 98 mmol), benzaldehyde (10.43 ml, 102.90 mmol), n-butylamine (0.49 ml, 4.90 mmol) and acetic acid (0.28 ml, 4.90 mmol) in 49 ml of toluene were heated at 180° C. in a Dean-Stark apparatus for 6 h. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The residue was taken up in 49 ml of toluene, benzaldehyde (10.43 ml, 102.90 mmol), n-butylamine (0.49 ml, 4.90 mmol) and acetic acid (0.28 ml, 4.90 mmol) were added, and the mixture was heated at 180° C. in a Dean-Stark apparatus for 3 h. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The residue was triturated with 25 ml of diethyl ether/pentane (1:1). The solid was filtered off, rinsed with cyclohexane, and dissolved in 75 ml of DCM. The solution was dried with magnesium sulfate and evaporated to dryness to give 21.57 g of the title compound as a yellow solid melting at 111-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]C)[C:5](N)=[N:6][CH:7]=1.N(OC(C)(C)C)=O>C(O)(=O)C.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][C:5]2=[N:6][CH:7]=1
Reactant: CSc1ccccc1-c1cc(Cl)cnc1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Clc1cnc2sc3ccccc3c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Solution of 5-chloro-3-(2-(methylthio)phenyl)pyridin-2-amine (5.2 g, 19.3 mmol) in 50 mL of glacial acetic acid and 20 mL of THF was cooled down to −10° C. and tert-butyl nitrite (4.6 mL) was added dropwise. The reaction mixture was stirred overnight at 0° C., warmed to room temperature, diluted with 100 mL of water. Solid material was filtered and dried, providing 2.5 g of pure 3-chlorobenzothieno[2,3-b]pyridine.
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][C:21]([Cl:27])=[N:20]3)=[O:16])[C:9]=1[F:28])OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:21]1[CH:22]=[N:23][C:24]2[C:19]([N:20]=1)=[CH:18][C:17]([C:15]([C:10]1[C:11]([F:14])=[CH:12][CH:13]=[C:8]([OH:7])[C:9]=1[F:28])=[O:16])=[CH:26][CH:25]=2
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2ncc(Cl)nc2c1)c1c(F)ccc(O)c1F
Yield: 62.1 %

Procedure:
A solution of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4-difluorophenyl) carbonate (42 mg, 0.1 mmol, 1.0 eq.) in TFA/DCM (1.5 mL/1.5 mL) was stirred at rt for 2 h, then concentrated. The residue was purified via flash column chromatography (PE/EA=4/1, v/v) to afford (3-chloroquinoxalin-6-yl)(2,6-difluoro-3-hydroxyphenyl)methanone as a yellow solid (19.9 mg) LRMS (M−H+) m/z calculated 319.0, found 318.9. 1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1 H), 8.31-8.34 (m, 2 H), 8.18-8.20 (d, 1 H), 7.08-7.14 (m, 1 H), 6.86-6.88 (m, 1 H), 5.43 (s, 1 H).
Reaction SMILES: C(C1C=C(F)C(N[C@@H](C(C)(C)C)CS(N)(=O)=O)=NC=1C1C2C(=NC=C(F)C=2)NC=1)#[N:2].[F:31][C:32]1[C:33]([NH:58][C@@H:59]([C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:60][S:61]([OH:64])(=[O:63])=[O:62])=C[C:35]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([F:47])[CH:45]=3)[N:40](S(C3C=CC(C)=CC=3)(=O)=O)[CH:39]=2)=[N:36][CH:37]=1.C(O)(C(F)(F)F)=O>C(#N)C.O>[F:31][C:32]1[C:33]([NH:58][C@@H:59]([C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:60][S:61]([OH:64])(=[O:63])=[O:62])=[N:2][C:35]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[C:44]([F:47])[CH:45]=3)[NH:40][CH:39]=2)=[N:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)[C@@H](CS(N)(=O)=O)Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
Sulfonic acid, 11, was synthesized in a manner similar to compound 30, using compound 57a: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>C1COCC1>[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:21][NH:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([CH:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)=[CH:23][CH:22]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: CC1CCC(N2CCN(c3ccc(C(=O)NN)cc3)CC2)CC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CC1CCC(N2CCN(c3ccc(C(=O)NNC(=O)c4ccc(I)cc4)cc3)CC2)CC1
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a suspension of 4-[4-(4-methylcyclohexyl)-1-piperazinyl]benzohydrazide (12.48 g) and pyridine (11.7 ml) in THF (374 ml) was added 4-iodobenzoyl chloride (11 g) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added water (3700 ml). The resulting precipitate was collected by filtration and dried to give N′-(4-iodobenzoyl)-4-[4-(4-methylcyclohexyl)-1-piperazinyl]benzohydrazide (22.45 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([N:19]3[CH2:23][CH2:22][C@@:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[C:25](=[O:32])[O:24]4)[CH2:20]3)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(#N)C.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[C:2](=[O:1])[CH2:7]1)(=[O:46])=[O:45]
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5=O)cc4)CC3)C2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)C(=O)C1
Reaction time: 3 h

Procedure:
To a solution of (1R)-1′-({1-[4-(2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (36 mg, 0.000083 mol) in acetonitrile (0.5 mL, 0.01 mol) were added triethylamine (29 μL, 0.00021 mol) and methanesulfonyl chloride. After stirring at it for 3 hours, the crude product was isolated and purified by prep-HPLC. LC/MS: 510.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][S:9][C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][S:9][C:10]2[C:15]([O:16][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2ncccc2O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CBr
Product: CCCc1c(CSc2ncccc2OCC(=O)OCC)ccc(C(C)=O)c1O
Yield: 70.8 %

Procedure:
Using as starting materials 0.10 g of 2-[(4-acetyl-3- hydroxy-2-propylbenzyl)thio]-3-hydroxypyridine obtained in Example 17 and 0.07 g of ethyl bromoacetate, 0.09 g of ethyl [[2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]pyridin-3-yl]- oxy]acetate was obtained in a manner similar to Example 15.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[Li]CCCC.CON(C)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:25].O>C1COCC1>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][C:11]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Reactant: CON(C)C(=O)c1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(-c2ccc(C(=O)c3ccccn3)s2)c(C)[nH]c1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-ethyl-6-methyl-5-thiophen-2-yl-1H-pyridin-2-one prepared in accordance with the procedures of Example 24, Step 3 (100 mg, 0.456 mmol) in anhydrous THF (3 ml) is cooled to −78° C., and n-BuLi (2.5 M in hexane, 0.4 ml, 1 mmol) is added. The resulting dark green mixture is stirred for 20 min, and then N-methoxy-N-methylpyridine-2-carboxamide (83 mg, 0.5 mmol) in THF (1 ml) is added. The reaction mixture is then added to water (5 ml) and extracted with ethyl acetate. The organic phases are washed and dried, and the residue is purified on silica gel. The product is dissolved in a minimal amount of methanol and treated with HCl in diethyl ether. The resulting brown precipitate is filtered off with suction and dried (12 mg, as hydrochloride). MS: m/e=325 (M+H). 1H-NMR (D6-DMSO, δ ppm) 11.85 (s, 1H); 8.81 (d, 1H); 8.30 (d, 1H); 8.12 (m, 2H); 7.71 (m, 1H); 7.44 (s, 1H); 7.29 (d, 1H) 3.37 (m, 2H); 2.50 (s, 3H); 1.14 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:6]=1.[CH3:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[CH:23]=O.CCOCC>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([CH:1]=[CH:23][C:16]2[N:15]([CH3:14])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=2)=[N:6][N:5]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: Cc1nnc(-c2ccccc2Cl)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nnc(-c2ccccc2Cl)s1
Yield: 53.4 %

Procedure:
21 g of 2-methyl-5-(2-chlorophenyl)-1,3,4-thiadiazole and 15.5 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde are heated with 0.5 g of ZnCl2 in a mixture of 100 ml of acetic acid and 50 ml of acetic anhydride for 6 hours at reflux temperature. After cooling, ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamide. 18.5 g of product is obtained, corresponding to 53% of the theory. The compound melts at 239° C.
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=[O:21])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:4]4[CH2:5][CH2:6][CH:7]([N:8]5[CH2:14][CH2:13][C:12]6[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=6[NH:10][C:9]5=[O:21])[CH:2]([F:1])[CH2:3]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1F)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1F)C(=O)N2

Procedure:
60 mg (0.21 mmol) 3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.30 mmol) TEA were stirred overnight in 1 mL DMF at RT. The reaction mixture was combined with 2 mL MeOH and the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:31])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:31].[ClH:31].[Cl:31][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[N:24]=[C:23]2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(N3CCOCC3)c3cc(Cl)ccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Clc1ccc2nc(NC3CCNCC3)nc(N3CCOCC3)c2c1

Procedure:
A solution of 4-(6-chloro-4-morpholin-4-yl-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.34 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 348.4 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[NH:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)C.CCOC(C)=O>[CH:22]1([NH:25][C@H:3]2[CH2:4][CH2:5][C@H:6]3[C@H:7]4[C@H:17]([CH2:18][CH2:19][C@:2]23[CH3:1])[C@:15]2([CH3:16])[C:10]([NH:11][C:12](=[O:20])[CH2:13][CH2:14]2)=[CH:9][CH2:8]4)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: C[C@]12CCC(=O)NC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Aza-androst-5(6)-ene-3,17-dione (0.53 g, 1.844 mmol) dissolved in chloroform (CHCl3, 10.0 mL) and cyclopropylamine ((CH2)2CHNH2, ALDRICH, 4.12 g, 72.15 mmol) is added, and the reaction mixture is heated to reflux under nitrogen. After 15 hours, the reaction is cooled to room temperature and analysis indicates the stoichiometric conversion to the cyclopropylimine. Sodium borohydride (NaBH4, ALPHA, 0.3574 g, 0.4475 mmol) in ethanol (21 mL) is added and the reaction is stirred at room temperature under nitrogen. After 21 hours, the reaction is worked-up by diluting with EtOAc (50 mL), washing in water (2×40 mL), in brine (40 mL) and drying over MgSO4, filtering and evaporating the solvent to obtain the crude product of the title compound. The crude product is further purified by flash chromatography (10.5″, 5.25 g, SiO2; elute first with 25% EtOAc/×25% CH2Cl2/50% hexane then with 15% iPrOH/×85%×CH2Cl2) to give 17β-cyclopropylamino-4-aza-androst-5(6)-en-3-one in excellent purity (0.4948 g, 1.5063 mmol). Yield: 82%.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[CH:23]=3)[C:19]3[C:30](=[O:40])[N:31](C(OC(C)(C)C)=O)[CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1.CCO>CO>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH:27]4[CH2:29][CH2:28]4)[CH:23]=3)[C:19]3[C:30](=[O:40])[NH:31][CH2:32][C:18]=3[C:17]=2[F:41])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C3CC3)ns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CO
Product: N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C3CC3)ns2)c2c(c1F)CNC2=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirred solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-cyclopropylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (58.9 mg, 0.100 mmol) in MeOH (2.0 mL) was added 4N HCl/dioxane (2.0 mL, 8.00 mmol). The reaction mixture was heated to 60° C. for 1 hour and then concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to give a yellow solid, which was suspended into EtOH. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with EtOH to give a hydrochloride salt of the title compound as an off-white solid (26.5 mg, 62%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.82-0.92 (m, 2H), 0.95-1.06 (m, 2H), 1.70-1.85 (m, 1H), 2.07-2.17 (m, 1H), 2.18-2.26 (m, 1H), 3.56-3.66 (m, 1H), 3.72-3.84 (m, 2H), 3.95-4.08 (m, 2H), 4.26-4.36 (m, 1H), 4.41-4.53 (m, 2H), 7.46 (d, J=4.88 Hz, 1H), 8.02 (br s, 3H), 8.68 (s, 1H), 8.72 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C18H20FN5O2S, 390. found, 390.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11](=[C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23]3)[S:10]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[CH2:14]([N:13]1[C:12](=[O:21])[C:11](=[C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2)[S:10][C:9]1=[N:8][C:4]1[CH:3]=[C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1C(=C2SC(=Nc3cccc(N)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Reactant: O=C1CCC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN1C(=C2SC(=Nc3cccc(NC(=O)CCC(=O)O)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a 25 mL flask was added 2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one (100 mg, 225 μmol), anhydrous DCM (5 mL) and CHCl3 (3 mL). To the solution was added succinic anhydride (23 mg, 239 μmol). The reaction solution was allowed to stir at 50° C. for 1.5 h. The white precipitates were collected by filtration under reduced pressure, washed with DCM (10 mL) and hexanes (20 mL), and then dried under vacuum to give the title compound (75 mg, 61%). MS(ESI): 545 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][N:12]([C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:25])[C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1nc(=O)[nH]cc1F
Reactant: CCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCOC(=O)n1cc(F)c(N(C)Cc2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To a stirred solution of 4-(benzyl(methyl)amino)-5-fluoropyrimidin-2(1H)-one (0.200 g, 0.858 mmol) in CH2Cl2 (18 mL) were added N-pentyl chloroformate (0.142 g, 0.944 mmol) and Et3N (0.263 mL, 1.88 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred an additional 3 h. The crude reaction mixture was evaporated to dryness and the residue was triturated with methyl t-butyl ether (MTBE; 4×5 mL) to remove triethylamine hydrochloride. The combined organic layers were evaporated in vacuo. The crude product was purified by reverse phase chromatography. Pentyl 4-(benzyl(methyl)amino)-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (20.1 mg, 6.7%) was isolated as a yellow gum: 1H NMR (methanol-d4) δ 8.04 (d, J=6.2 Hz, 1H), 7.38-7.25 (m, 5H), 4.24 (t, J=6.6 Hz, 2H), 3.21 (d, J=3.3 Hz, 2H), 1.78-1.65 (m, 3H), 1.37 (dd, J=9.2, 5.5 Hz, 6H), 0.92 (t, J=7.1 Hz, 3H); ESIMS m/z 348 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([O:15]CC)=[O:14].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1[nH]nc(-c2ccncc2)c1C(=O)O
Yield: 88.1 %

Procedure:
To a solution of ethyl 5-methyl-3-(pyridin-4-yl)-1H-pyrazole-4-carboxylate (3.1 g) in ethanol (20 mL) were added sodium hydroxide (8.0 g) and water (10 mL), and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, the pH of the mixture was adjusted to 5 with 2 N hydrochloric acid, and mixture was concentrated under reduced pressure. The obtained solid was collected by filtration and washed with water to give the title compound (2.4 g).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15].[NH4+].[Cl-]>C(Cl)Cl>[O:6]([CH2:1][CH2:2][C@H:3]([OH:5])[CH3:4])[Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](O)CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (R)-1,3-butanediol (2 g), triethylamine (4 mL) and t-butyldiphenylchlorosilane (6.7 g) in CH2Cl2 (80 mL) was stirred at r.t. for 15 h. Saturated NH4Cl was added and the mixture was extracted with ethyl acetate. The combined organics were dried (MgSO4) and concentrated. Flash chromatography of the residue (9:1 hexane/ethyl acetate) provided the title compound as an oil.