Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C:12]2([F:17])[F:16])C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:16][C:12]1([F:17])[CH2:11][C@H:10]2[CH2:15][C@@H:13]1[CH2:14][C@@H:9]2[OH:8]
Reactant: FC1(F)C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Palladium (10 wt. % on activated carbon, 0.28 g) was added to a solution of (1R,4R,5S)-5-(benzyloxy)-2,2-difluorobicyclo[2.2.1]-heptane (1.43 g, 6.0 mmol) in methanol (15 mL), and the mixture was placed under a balloon full of hydrogen.After stirring at ambient temperature for 4 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was adsorbed onto a small pad of silica gel, and eluted with 20% of ethyl acetate in hexanes. The solvents were removed in vacuo to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18]C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39](=[O:41])[CH3:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C[Si](Cl)(C)C>CCCCO>[NH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][N:11]([C:4]2[N:3]=[C:2]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:34][CH2:35][N:36]([C:39](=[O:41])[CH3:40])[CH2:37][CH2:38]4)=[CH:31][CH:32]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH2:16][CH2:15]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)nc3[nH]cnc23)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(CN)CC4)c4nc[nH]c4n3)cc2)CC1
Yield: 9.8 %

Procedure:
A mixture of tert-butyl (1-(2-chloro-9H-purin-6-yl)piperidin-4-yl)methylcarbamate (100 mg, 0.272 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (120 mg, 0.548 mmol) and trimethylsilyl chloride (0.300 mL, 2.37 mmol) in n-BuOH (4 mL) was stirred at 135° C. for 70 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 450.6 (M+H); UV 200.0, 270.8 nm.
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.Cl.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][CH:43]=2)=[CH:34][CH:33]=1.[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69](Cl)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69]([N:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=3)=[CH:43][N:42]=2)[CH2:49][CH2:48]1)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Clc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 80.9 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-butyl ester, from 4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine dihydrochloride (0.228 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.295 g), to yield the title compound as a yellow solid (0.325 g, 81%).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Ni]>[O:11]1[C:12]2[C:4]([NH2:1])=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1OCC2
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc2c1OCC2

Procedure:
39.4 g of 2,3-dihydro-7-nitrobenzofuran (prepared by the method described in Journal of Heterocyclic Chemistry, vol. 5, No. 1, p. 1 (1968)) in 200 ml of tetrahydrofuran was hydrogenated in a Parr shaker (50 p.s.i.g. hydrogen pressure, Raney nickel catalyst, 3 hours, room temperature). The resulting mixture was filtered and the solvent was evaporated from the filtrate. The residue was recrystallized from ether to give 1, as a colorless solid, m.p.: 70°-72° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.Cl.[N:16]1[C:25]2[C:20](=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[C:7]([C:4]1[C:3]([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[C:2]([NH:1][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][CH:17]=[N:16]3)[S:6][CH:5]=1)#[N:8]
Reactant: N#Cc1csc(N)c1-c1cnccn1
Reactant: O=C(O)Cc1cccc2ncccc12
Agent: Cl
Product: N#Cc1csc(NC(=O)Cc2cccc3ncccc23)c1-c1cnccn1

Procedure:
The title compound was synthesized from 5-amino-4-(pyrazin-2-yl)thiophene-3-carbonitrile (30.5 mg, 0.15 mmol) and 2-(quinolin-5-yl)acetic acid hydrochloride (36 mg, 0.16 mmol) according to protocol A. The product was purified by HPLC method [4], retention time=1.393 min; MS (ESI) 372.1 (MH+); 1H NMR (300 MHz, CD3OD) δ 9.30 (d, J=1.5 Hz, 1H), 9.06 (dd, J=4.8, 1.3 Hz, 1H), 8.99 (d, J=8.5 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.29 (t, J=1.9 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.09 (dd, J=8.6, 7.1 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J=6.7 Hz, 1H), 7.86 (dd, J=8.6, 4.9 Hz, 1H), 4.55 (s, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]1.I[CH3:24]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[N:15]1[C:20](=[O:21])[N:19]([CH3:24])[C:18](=[O:22])[CH:17]=[N:16]1
Reactant: CC(C)Oc1cc(-n2ncc(=O)[nH]c2=O)c(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(-n2ncc(=O)n(C)c2=O)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 0.6 g (0.025 mole) of sodium hydride in 15 mL of N,N-dimethylformamide was added a solution of 7.5 g (0.024 mole) of 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione in 30 mL of N,N-dimethylformamide with external cooling to maintain the reaction temperature below 40° C. After complete addition, the mixture was allowed to come to room temperature and was stirred for one hour. A solution of 3.5 g (0.025 mole) of iodomethane in 10 mL of N,N-dimethylformamide was added to the reaction mixture, and stirring was continued for an additional hour at room temperature. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to produce 2-[2,4-dichloro-5-(1-methylethoxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as an oil, Compound 12 in the tables.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:13]1[CH:12]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cccc(-c2ccccc2)c1
Yield: 78.8 %

Procedure:
A mixture of phenylboronic acid (1.000 g, 8.20 mmol), methyl 3-bromophenylacetate (1.691 g, 7.38 mmol), Na2CO3 (1.738 g, 16.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.474 g, 0.41 mmol), toluene (30 mL), and water (5 mL) was heated under reflux for 20 h. The reaction mixture was diluted with water (20 mL) and the volatiles were removed in vacuo. The aqueous solution was washed with EtOAc (4×20 mL). The organic solutions were combined, washed with 1N NaOH (15 mL) followed by water (15 mL). The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (79:1 hexanes:EtOAc to 39:1 hexanes:EtOAc) provided biphenyl-3-yl-acetic acid methyl ester (1.316 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:26][CH:23]([CH3:25])[CH3:24])=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NC(C)C)c(Br)c2)c(SC)s1
Temperature: 70 °C

Procedure:
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol), (Example 2: step c), isopropylamine (0.012 g, 0.204 mmol), THF [2.0 mL]. Reaction vessel was sealed and heated to 70° C. for 72 hours. Removal of the solvents in vacuo followed by chromatography (0%–15% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C15H17BrN2O4S3: 466.41 (M+H); found 466.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:13][CH2:12]1)[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-methylcyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.23 mmol) in dichloromethane (3 mL) was added triethylamine (3 mL) and isobutyryl chloride (28 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 12 h and then quenched with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:1) as eluent to obtain 5-cyclohex-1-enyl-3-[(1-isobutyryl-piperidin-4-yl)-(trans-4-methyl cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (55 mg, 47%) as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:15].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11]([I:15])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)NC(=O)c1ncc(Br)cn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ncc(I)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
5-Bromo-pyrimidine-2-carboxylic acid tert-butylamide (Example 9, step 1) (950 mg, 3.68 mmol) was dissolved in dioxane (10 ml). Sodium iodide (2.2 g, 14.7 mmol, 4 equiv.), copper(I)iodide (66 mg, 0.74 mmol, 0.2 equiv.) and trans-N,N′-dimethylcyclohexane-1,2-diamine (CAS 67579-81-1) (105 mg, 0.74 mmol, 0.2 equiv.) were added and the mixture was stirred for 16 hours at 100° C. The reaction mixture was extracted with saturated NaHCO3 solution and two times with ethyl acetate. The organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired 5-iodo-pyrimidine-2-carboxylic acid tert-butylamide (870 mg, 78% yield) was obtained as a yellow solid, MS: m/e=306.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:36])[CH:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([Cl:34])[CH:28]=2)[CH3:24])=[O:16])[CH2:12][C:11](=[O:37])[O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>>[CH2:1]([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:36])[CH:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:29]([Cl:34])[CH:28]=2)[CH3:24])=[O:16])[CH2:12][C:11](=[O:37])[O:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Product: CC(NC(=O)c1ccc(NC(=O)C(C)(C)C)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a suspension of 98b (100 mg, 0.19 mmol) and poly(4-vinylpyridine) (200 mg) was added pivaloyl chloride (70 μL, 0.57 mmol). The resulting suspension was stirred overnight at room temperature the filtered and diluted with EtOAc (25 mL). The organic layer was washed with 10% NaHCO3 (2×25 mL), saturated NaCl (1×25 mL), dried (MgSO4), and evaporated to dryness to afford 98 mg of title compound (85% yield) after chromatography. 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.10-1.55 (m, 3H), 1.38 (s, 9H), 1.65-2.40 (m, 4H), 2.60-3.10 (m, 2H), 3.46-3.88 (m, 2H), 4.20-4.95 (m, 5H), 5.62 (d, 0.8H), 5.78 (d, 0.2H), 7.15-8.30 (m, 8H). Analytical HPLC: 11.82 min. LC-MS (ES+): m/e=613.2 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([Cl:22])=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:19][C:18]=2[CH:28]=1>CN(C)C=O>[Cl:22][C:21]1[C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:3]3[C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:9]=4[N:1]=[CH:2]3)=[CH:28][C:18]=2[S:19][C:20]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Reactant: c1cc2[nH]cnc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(Cn3cnc4ccncc43)ccc2c1Cl
Reaction time: 0.67 h
Yield: 14.3 %

Procedure:
1H-Imidazo[4,5-c]pyridine (536 mg, 4.5 mmol) was added in portions to a stirred suspension of sodium hydride (144 mg of 60% dispersion in mineral oil, 3.6 mmol) in anhydrous dimethylformamide (5 ml) at 0° C., under a nitrogen atmosphere. After 40 minutes, ethyl 6-bromomethyl-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 10, 1 g, 3 mmol) was added. After 20 hours the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 5% methanol in dichloromethane as eluant The fractions containing the less polar product (first isomer eluted from the chromatography column) were evaporated under reduced pressure to give the title compound as a colourless solid (160 mg).
Reaction SMILES: N1C(C)=CC=CC=1C.Cl[CH2:10][N:11]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:12]([Cl:15])(=[O:14])=[O:13].C1CCCCC1.[CH3:28][OH:29]>>[CH3:28][O:29][CH2:10][N:11]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:12]([Cl:15])(=[O:14])=[O:13]
Reactant: CO
Reactant: O=S(=O)(Cl)N(CCl)C1CCCCC1
Solvent: Cc1cccc(C)n1
Solvent: C1CCCCC1
Product: COCN(C1CCCCC1)S(=O)(=O)Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
22 parts of 2,6-lutidine are added in the course of 15 minutes, at from -5° to +5° C., to a mixture of 50 parts of N-chloromethyl-N-cyclohexylsulfamic acid chloride in 110 parts of cyclohexane and 55 parts of methanol. The reaction mixture is stirred for 20 minutes at 25° C. and one hour at 45° C. After concentrating the solvent under reduced pressure and removing the hydrochloride which has precipitated, distillation gives 30 parts (60% of theory) of N-methoxymethyl-N-cyclohexylsulfamic acid chloride of boiling point 102°-106° C./0.01 mbar and nD25 =1.4857.
Reaction SMILES: Cl.[C:2]([C@@H:5]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])[NH2:3].C=O.[BH3-][C:42]#N.[Na+]>CO>[C:2]([C@@H:5]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:21][CH2:22][CH:23]([N:26]([CH3:42])[CH3:27])[CH2:24][CH2:25]4)[C:9]=3[C:8]1=2)(=[O:4])[NH2:3]
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A solution of benzyl N-[(1S)-1-carbamoyl-2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl]carbamate hydrochloride (100 mg, 0.18 mmol, 1.00 equiv) in methanol (10 mL) was added HCHO (37%, 2 mL) and stirred for 0.5 h at room temperature. This was followed by the addition of NaBH3CN (33.6 mg, 0.53 mmol, 2.99 equiv) at 0° C. and the resulting solution was allowed to react, with stirring, for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and extracted with 3×50 mL of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with CH2Cl2: CH3OH (10:1) to provide benzyl N-[(1S)-1-carbamoyl-2-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl]carbamate (50 mg, 52%) as a white solid.
Reaction SMILES: [N+](C1C=C(S(O[C:14]2[NH:15][S:16](=[O:25])(=[O:24])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)(=O)=O)C=CC=1)([O-])=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CC(C)=O>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:14]2[NH:15][S:16](=[O:24])(=[O:25])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:29][CH2:28]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC2=Nc3ccccc3S(=O)(=O)N2)c1
Reactant: CN1CCNCC1
Solvent: CC(C)=O
Product: CN1CCN(C2=Nc3ccccc3S(=O)(=O)N2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a stirred suspension of 1.0 g of 3-(m-nitrobenzenesulfonyloxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide in 10 ml of acetone is added dropwise 0.53 g of 1-methylpiperazine, while the mixture is cooled in an ice bath. After the addition, the mixture is stirred at room temperature for 1 hour. After removal of acetone by distillation under reduced pressure, 30 ml of water is added to the residue. The crystalline precipitate is collected by suction filtration and treated with 2 ml of a 10% aqueous sodium hydroxide solution. After removal of the insoluble materials by suction filtration, the filtrate is adjusted to a pH 8.0 with dilute hydrochloric acid. The crystalline precipitate is collected by suction filtration and recrystallized from a mixture of dimethylformamide and water to give 0.2 g of the desired product, m.p. 265°-267° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:27]([CH:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:31]1C(O)=O)(O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[O:28])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)piperazine-1-carboxamide (2.00 g, 7.30 mmol) in DMF (150 ml) was added DIPEA (3.8 ml, 21.9 mmol), 3-carboxy-N-boc-proline (Arch Corporation) (1.727 g, 8.02 mmol) and HATU (3.051 g, 8.02 mmol) and the reaction stirred at ambient temperature for overnight (convenience). The solvents were then removed under reduced pressure. The resulting gum was then partitioned between EtOAc and water, extracted, the organic phase washed with saturated sodium bicarbonate solution and evaporated to dryness. The resulting foam was then purified on Isco™ Companion (40 g column:EtOAc) to give the product tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate as a pale yellow foam (3.396 g, 7.20 mmol, 99%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=[C:9]3[O:18][CH3:19])[CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]3[O:18][CH3:19])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(OC)c2cccc(C3CC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)nc2c(C3CC3)cccc12
Reaction time: 1 h

Procedure:
30.0 g of methyl 8-cyclopropyl-4-methoxyquinoline-2-carboxylate, 250 ml of THF and 400 ml of MeOH was placed in 2 L-flask, and 46 ml of 5N NaOH aq. was added, and stirred for 1 h. The mixture was concentrated in vacuo and diluted with water. 46 ml of 5N HCl aq. was added with cooling in ice bath, extracted with 500 ml of CHCl3-MeOH (4-1), dried over Na2SO4 and filtered. The filtrate was concentrated to afford a yellow solid. The solid was washed with hexane-CHCl3, filtered and dried under vacuum to afford 8-cyclopropyl-4-methoxyquinoline-2-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][CH2:7][CH:8]([CH3:10])[CH3:9].[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>>[Br:12][CH:13]([CH3:17])[C:14]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][CH2:7][CH:8]([CH3:9])[CH3:10])=[O:15]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)COC(=O)NCCO
Product: CC(C)COC(=O)NCCOC(=O)C(C)Br

Procedure:
by using isobutyl 2-hydroxyethylcarbamate and 2-bromopropionyl bromide there is obtained isobutyl 2-(2-bromopropionyloxy)-ethylcarbamate, nD20 1.4731;
Reaction SMILES: OC[C@@H](N[C:11](=[O:26])[C@@:12]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[CH3:25][C@:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:11]([OH:26])=[O:28]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 98 %

Procedure:
To a solution of Example 49A (3.78 g, 10.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.47 g, 98%). 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9 H) 1.09 m, 2 H) 1.56 (s, 3 H) 1.99 m, 2 H) 7.33 m, 5 H).