Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:20][C:21]([C:23]2[C:31]3[CH:30]=[C:29]([C:32]4[C:37]([CH3:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=4)[S:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:34]2[N:33]=[C:32]([C:29]3[S:28][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:21](=[O:22])[NH:20][CH:17]5[CH2:19][CH2:18]5)[C:31]=4[CH:30]=3)[C:37]([CH3:38])=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NCCC2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
4-(2-Aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.22 g, 5.35 mmol) is added to a stirred suspension of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.736 g, 2.14 mmol) and diisopropylethylamine (1.12 mL, 6.42 mmol) in anhydrous 1,4-dioxane (8 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 97° C. for 48 hours. At room temperature the mixture is concentrated and chromatographed on silica gel, eluting with CH3OH in dichloromethane: 0-4%, to give 4-{2-[4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-5-methyl-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1COCC1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.CCN(C(C)C)C(C)C>CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc(Cl)nc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
A mixture of 2,6-dichloronicotinic acid (19.2 g, 0.1 mol), N,N′-carbonyldiimidazole (CDI, 17.8 g, 0.11 mmol) and THF (1 L) was stirred at 60° C. for 30 min and cooled to room temperature. To the mixture was added 3-aminomethylpyridine (10.2 mL, 0.1 mol) and DIEA (21 mL, 0.12 mol). The reaction mixture was stirred at room temperature for 4 hrs, and diluted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4. Concentration of the organic solution gave 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.5 g, 73%). LRMS (M+H+) m/z 282.0; (M+2+H+) m/z 283.9.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1Cl
Temperature: 0 °C
Yield: 82.7 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 92, 200 mg, 0.61 mmol) and stirred at 0° C. for 20 min and then warmed to 25° C. where it was stirred for 30 min. After such time, the reaction mixture was treated with 2-amino-5-bromopyridine (157 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-bromo-pyridin-2-yl)-propionamide (245 mg, 83%) as a white foam: EI-HRMS m/e calcd for C20H22Br ClN2O3S (M+) 484.0223, found 484.0222.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].N(C1C2CCCCC=2C(C#N)=CC=1)=[C:16]=[O:17]>>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH3:14])=[C:16]=[O:17]
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Product: Cc1c(N=C=O)ccc(C#N)c1C(F)(F)F

Procedure:
The title compound was prepared from 18D in a manner similar to that described in Experiment 2E.
Reaction SMILES: [OH:1][C@:2]1([C:43](O)=[O:44])[CH2:19][C@H:18]([O:20][C@@H:21]2[O:35][C@@H:34]([CH3:36])[C@H:24]3[O:25][C@H:26]4[N:31]([C@H:23]3[CH2:22]2)[CH2:30][CH2:29][O:28][C@@H:27]4[O:32][CH3:33])[C:17]2[C:4](=[C:5]([OH:42])[C:6]3[C:7](=[O:41])[C:8]4[C:13]([C:14](=[O:38])[C:15]=3[C:16]=2[OH:37])=[C:12]([O:39][CH3:40])[CH:11]=[CH:10][CH:9]=4)[CH2:3]1.C(N(CC)CC)C.[NH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[OH:42][C:5]1[C:4]2[CH2:3][C@@:2]([OH:1])([C:43]([N:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)=[O:44])[CH2:19][C@H:18]([O:20][C@@H:21]3[O:35][C@@H:34]([CH3:36])[C@H:24]4[O:25][C@H:26]5[N:31]([C@H:23]4[CH2:22]3)[CH2:30][CH2:29][O:28][C@@H:27]5[O:32][CH3:33])[C:17]=2[C:16]([OH:37])=[C:15]2[C:6]=1[C:7](=[O:41])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([O:39][CH3:40])[C:13]=1[C:14]2=[O:38]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)O)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: C1CNCCN1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)N1CCNCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of 56 (9 mg) in anhydrous dichloromethane (5 ml) under argon atmosphere, anhydrous triethylamine (1.6 mg, 0.0158 mmol), piperazine (3.6 mg, 0.0424 mmol), HOBt (2.1 mg, 0.0158 mmol) and EDC (3.0 mg, 0.0158 mmol) were added. The reaction mixture was stirred at room temperature over night. The solvent was evaporated under vacuum and the residue was then purified by flash column chromatography (DCM/MeOH/AcOH/H2O 45/4/1/0.5) on silica gel (230-400 mesh). The product obtained was dissolved in DCM and washed with satd. NaHCO3 (x2) and water (x2). The organic solvent was evaporated under vacuum to afford 5.0 mg of 57. MS (ESI): 696 [M+H]+. Retention time=4.01 min (method 1, Example 3b).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].[CH2:18]([Cl:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[Cl-:25].[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2+:16][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)CCCCCCCCCCCCCN
Reactant: ClCc1ccccc1
Solvent: O
Product: CC(C)CCCCCCCCCCCCC[NH2+]Cc1ccccc1
Product: [Cl-]
Yield: 65 %

Procedure:
Dimethylmyristylbenzylammonium chloride was synthesized from dimethylmyristylamine and benzyl chloride by a conventional method and the water content of the product was adjusted to 19%. 90 Kg of the mixture (viscosity 60
Reaction SMILES: Cl[C:2]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:3].[NH2:9][CH:10]1[N:14]=[C:13]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:21]=[C:12]2[S:11]1.N1C=CC=CC=1>C(Cl)Cl>[S:11]1[C:12]2=[CH:21][C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:13]2=[N:14][CH:10]1[NH:9][C:2](=[O:3])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NC1N=C2C(=Cc3ccccc32)S1
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)NC1N=C2C(=Cc3ccccc32)S1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
4.2 g (0.031 mole) of ethyl chloroformylformate were added dropwise at room temperature to a solution of 5.2 g (0.028 mole) of 2-amino indeno[1,2-d]thiazole in 250 ml of methylene chloride/2.5 ml of pyridine. The reaction mixture was stirred overnight, after which it was washed with water and dried over Na2SO4, the solvent was distilled off and the residue was recrystallized from acetone to give 5.0 g (62%) of a product of melting point 226°-228° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:34]=[N:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:35]6[CH:36]=[N:31][CH:32]=[N:33][CH:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: NC1(c2cncnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cncnc5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.041 g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylehtylamine (0.162 g, 1.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for overnight. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally it was purified by preparative HPLC. Yield: 0.02 g (20%). 1H NMR (400 MHz, DMSO-d6): δ 1.34-1.35 (m, 2H), 1.41-1.42 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, 3H), J=4.56 Hz), 738-7.45 (m, 4H), 7.58 (d, 1H, J=0.96 Hz), 7.75 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.83 (m, 1H), 7.98-8.01 (m, 2H), 8.46-8.47 (d, 1H, J=4.6 Hz), 8.64 (s, 2H), 9.01 (s, 1H), 9.31 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH Flow: 1 ML/Min
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[C:37]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)[CH:38]=1)[NH2:35]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:35][C:34]2[CH:36]=[C:37]([N:39]3[CH:43]=[N:42][N:41]=[N:40]3)[CH:38]=[C:32]([O:31][CH3:30])[CH:33]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: COc1cc(N)cc(-n2cnnn2)c1
Product: COc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)cc(-n2cnnn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-methoxy-5-(1H-tetrazol-1-yl)aniline in step 1. MS: 425.4 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH3:12])=[O:5])C.O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[Br:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:12])[N:8]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.0 g, 12 mmol) in tetrahydrofuran (THF, 50 mL) and water (5 mL) was added lithium hydroxide hydrate (1.0 g, 24 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was made acidic to pH 1 with 2 N hydrochloric acid (HCl) and then was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate (Na2SO4), filtered and concentrated to provide product as an orange solid (2.6 g, 98%): mp 152-155° C.; 1H NMR (300 MHz, CDCl3) δ 2.74 (s, 3H); ESIMS m/z 221 (M−1).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([OH:9])=[O:8])([CH3:4])[CH3:3].[P:10]([OH:13])([OH:12])[OH:11].Cl.[CH2:15]=O>O.C(O)C>[CH:2]([N:5]([CH2:15][P:10]([OH:13])([OH:12])=[O:11])[CH2:6][C:7]([OH:9])=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)O
Reactant: OP(O)O
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)N(CC(=O)O)CP(=O)(O)O
Temperature: 108 °C
Yield: 64.3 %

Procedure:
To a 5 L 3-necked flask fitted with a mechanical stirrer, thermometer, addition funnel, and condenser was added 363 g (2.37 mol) of N-isopropylglycine hydrochloride, 205 g (2.50 mol) of phosphorous acid, and 1.7 L of 20% HCl solution. The mixture was heated to 108° C. giving a solution. From the addition funnel 231 g (2.84 mol) of 37% formaldehyde solution was added to the hot reaction mixture over 2 hours. The resulting yellow solution was refluxed for 8.5 hours. All volatiles were removed by vacuum distillation to leave a yellow oil. The oil was dissolved in 300 ml of H2O and diluted with 500 ml of ethyl alcohol to cause precipitation of the product. The crystals were collected by filtration, washed with ethyl alcohol, and air dried to yield 322 g (64%) of N-isopropyl-N-phosphonomethylglycine. Additional product contained in the mother liquors was not isolated.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].C(N(CC)CC)C.CO[C:19]([C:21]1[N:26]=[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:24]2[N:34]([CH2:44][C@H:45]3[CH2:50][CH2:49][C@H:48]([CH3:51])[CH2:47][CH2:46]3)[C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[CH2:42][F:43])=[N:36][C:23]=2[CH:22]=1)=[NH:20]>C(O)C.CCOC(C)=O>[Cl:33][C:31]1[CH:32]=[C:27]([C:25]2[C:24]3[N:34]([CH2:44][C@H:45]4[CH2:50][CH2:49][C@H:48]([CH3:51])[CH2:47][CH2:46]4)[C:35]([N:37]4[CH2:41][CH2:40][CH2:39][C@H:38]4[CH2:42][F:43])=[N:36][C:23]=3[CH:22]=[C:21]([C:19](=[NH:20])[NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[N:26]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=N)c1cc2nc(N3CCC[C@H]3CF)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=N)c1cc2nc(N3CCC[C@H]3CF)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tert-butyl carbazate (106 mg, 0.802 mmol) and triethylamine (418 μL, 3.006 mmol) were added to a solution of crude methyl-4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-carbimidate (Example 14.2, Step 1; 50 mg, 0.100 mmol) in ethanol (100 μL) in a vial, and the reaction was capped and stirred at ambient temperature for 72 hr. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude tert-butyl 2-((4-(5-chloropyridin-3-yl)-2-((S)-2-(fluoromethyl)pyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)(imino)methyl)hydrazinecarboxylate. MS ESI calc'd. for C30H40ClFN8O2 [M+H]+ 599. found 599. This material was taken on to Step 2 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:34]=[CH:33][S:32][C:21]=4[C:22](=[O:31])[NH:23][C:24]=3[C:25]([Cl:30])=[CH:26][C:27]=2[O:28]C)[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6]C(=O)OC(C)(C)C.BrB(Br)Br>>[ClH:1].[NH2:6][CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][C:16]([C:18]2[C:19]3[C:20]4[CH:34]=[CH:33][S:32][C:21]=4[C:22](=[O:31])[NH:23][C:24]=3[C:25]([Cl:30])=[CH:26][C:27]=2[OH:28])=[CH:17][C:2]=1[Cl:1]
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(Cl)c1
Agent: BrB(Br)Br
Product: Cl
Product: NCCc1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1Cl
Yield: 108.8 %

Procedure:
Following General Procedure F, tert-butyl 2-chloro-4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (80 mg, 0.154 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.92 mL, 0.92 mmol) to afford the desired product (37 mg, 59%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.68 (d, J=5.4 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.42 (d, J=1.7 Hz, 1H), 7.30 (s, 1H), 7.27 (dd, J=7.8, 1.7 Hz, 1H), 6.17 (d, J=5.4 Hz, 1H), 3.39-3.25 (m, 4H); ESI MS m/z 405 [C19H14Cl2N2O2S+H]+; HPLC 98.1% (AUC), tR=9.17 min.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:11]1([S:10][C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[NH2:1])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=N[C@@H]1CCCC[C@H]1Sc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CCCC[C@H]1Sc1ccccc1

Procedure:
A room temperature solution of Example 7B (777 mg, 3.3 mmol), triphenylphosphine (2.62 g, 10.0 mmol), and water (180 mg, 10 mmol) in THF (5 mL) was stirred for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes followed by 10% methanol/dichloromethane to provide the desired product. MS (DCI) m/e 208 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[S:13][CH2:14][C:15]([OH:17])=O)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]2[S:13][CH2:14][C:15](=[O:17])[NH:1][C:4]=2[CH:9]=1
Reactant: O=C(O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)CS2
Yield: 61.7 %

Procedure:
A solution of 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 9 mmol) and tin (II) chloride dihydrate (22.6 g, 0.1 mol) in ethanol (30 mL) was refluxed overnight. After removal of the solvent under reduced pressure, the residual slurry was diluted with water (100 mL) and basified with 10% Na2CO3 solution to pH 8. The resulting suspension was extracted with ethyl acetate (3×100 mL). The ethyl acetate extract was washed with water and brine, dried over Na2SO4, and concentrated. The residue was washed with CH2Cl2 to yield 6-amino-2H-benzo[b][1,4]thiazin-3(4H)-one (DC-7) as a yellow powder (1 g, 52%). 1H NMR (DMSO-d6) δ 10.24 (s, 1H), 6.88 (d, 1H, J=6 Hz), 6.19-6.21 (m, 2H), 5.15 (s, 2H), 3.28 (s, 2H); ESI-MS 181.1 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.[CH:15](I)([CH3:17])[CH3:16]>C1COCC1.C([Li])(C)(C)C.O>[CH:15]([C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12)([CH3:17])[CH3:16]
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CC(C)I
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1sc(C(=O)O)c2c1CC(C)(C)CC2
Temperature: -78 °C
Reaction time: 3 h
Yield: 20.8 %

Procedure:
To a cooled solution (−78° C.) of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.00 g, 9.51 mmol) in THF (35 mL), tert.-butyllithium (16 mL, 1.5 M solution in pentane) is added. The mixture is stirred at −78° C. for 10 min before isopropyliodide (7.60 g, 48.7 mmol) is added. The reaction mixture is stirred at −78° C. for 3 h, then at rt for 3 d. The reaction mixture is diluted with water and extracted twice with EA. The combined organic extracts are dried over Na2SO4 and evaporated. The crude product is purified by CC on silica gel eluting with DCM/TBME 20:1 followed by prep. HPLC to give 3-isopropyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (500 mg) as a white solid; LC-MS: tR=1.04 min, [M+1+CH3CN]=294.16.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.C[Si]([N:29]=[C:30]=[O:31])(C)C.Cl.[OH-].[Na+]>ClCCl.O>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([C:30]([NH2:29])=[O:31])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c(C3CCNCC3)nc(Br)c12
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nccn2c(C3CCN(C(N)=O)CC3)nc(Br)c12
Reaction time: 0.25 h
Yield: 70 %

Procedure:
1-Bromo-8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (0.169 mmol, 50 mg) was dissolved in dichloromethane (1 ml) and triethylamine (0.545 mmol, 76 μl) and trimethylsilyl isocyanate (0.186 mmol, 25.3 μl) were added at 0° C. After stirring at room temperature for one hour water and 2N hydrochloric acid was added and stirred for 15 minutes. The reaction mixture was basified with 2 N aqueous sodium hydroxide until pH=10 and extracted three times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrate in vacuo to afford 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxamide (40 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23][CH3:24])[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:26](I)[CH3:27].CCN(C(C)C)C(C)C>CO>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23][CH3:24])[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[CH2:26][CH3:27])=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3)c2n1
Reactant: CCI
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3CC)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A portion of the solution (3 ml) containing 2-(butyloxy)-8-(methyloxy)-9-[2-(2-piperidinyl)ethyl]-9H-purin-6-amine (approx 140 mg, 0.402 mmol) was treated with ethyl iodide (0.032 ml, 0.402 mmol) and DIPEA (0.140 ml, 0.804 mmol). The reaction was stirred at ambient temperature in a capped vial overnight. Methanol was added to give solution and this was purified by MDAP (Method A). Product fractions were evaporated under N2 in a Radleys blow down unit. The title compound was obtained as a white solid (103 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].Cl[C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O.[OH-].[Li+].[ClH:24]>CS(C)=O>[Cl:24][C:16]1[CH:15]=[CH:14][C:13]([NH:1][C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=2[C:7]#[N:8])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])s1
Temperature: 0 °C
Yield: 33 %

Procedure:
Dissolve 2-amino-5-methyl-thiophene-3-carbonitrile (4.14 g, 30 mmol) and 2,4-dichloronitrobenzene (5.76 g, 30 mmol) in dimethylsulfoxide (70 ml) and stir under nitrogen. Add lithium hydroxide monohydrate (2.0 g, 47.7 mmol) and heat the mixture in an oil bath at room temperature for 18 hours. Pour the mixture into ice water, make acid with 2N HCl, extract into ethyl acetate, dry (MgSO4) and concentrate under reduced pressure. Crystallize from ethanol to give 2-(4-chloro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile as a yellow solid (2.92 g, 33%): NMR (1H, 300 MHz, CDCl3): δ 9.5 (1H broad), 8.25 (1H,s), 7.45 (1H, d), 7.1 (1H,d), 6.25 (1H, s), 2.5 (3H,s).