Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH3:30]
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 85.6 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is added dropwise to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, a solution containing 5.2 g (0.088 mol) of propylamine in 80 ml of chloroform is added dropwise at -15° C. during 30 minutes, then the mixture is stirred for 1 hour below -10° C. Then the mixture is allowed to stand overnight under cooling by ice. For working up, the chloroform mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The chloroform phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.8 g (85.6%) of the named product in the form of yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]#[N:5].[NH2:6][C:7]([NH2:9])=[S:8]>O>[ClH:1].[C:4]([CH2:3][CH2:2][S:8][C:7](=[NH:6])[NH2:9])#[N:5]
Reactant: N#CCCCl
Reactant: NC(N)=S
Solvent: O
Product: Cl
Product: N#CCCSC(=N)N
Reaction time: 1 h

Procedure:
The 3-chloropropanenitrile (4.32 g, 48.3 mmol) and thiourea (4.04 g, 53.1 mmol) are mixed in 40 ml of water. The mixture is heated to reflux for 3 to 4 hours. The reaction mixture is evaporated and 20 ml of ethanol is added and then evaporated as well. This is repeated three times. After that, 10 ml of methanol and 30 ml of acetone are added and the mixture is stirred for one hour. The crystalline material is filtered and the product is dried under high vacuum overnight to obtain S-(2-cyanoethyl)isothiourea hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:34][CH2:35][CH2:36]N.C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:36][CH2:35][F:34])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCCF
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCF)C1
Yield: 95 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoroethylamine hydrochloride, afforded the crude desired product (Note: 0.34 mmol of anhydrous sodium acetate was added to the reaction mixture to neutralise the amine). Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (80 mg, 95%). LCMS (method B): RT=3.68 min, M+H+=492.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 90 °C
Yield: 56.4 %

Procedure:
Imidazole (0.816 g, 0.01 mol), ethyl 4-fluorobenzoate (2 g, 0.01 mol) and anhydrous potassium carbonate (1.43 g, 0.011 mol) was dissolved in DMSO (30 ml) and heated to 90° C. for 18 h. The solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The white solid was purified by flash column chromatography (silica, diethyl ether) to afford a white solid (1.22 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.S(O[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=O)(=O)C.CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1

Procedure:
A solution of 49.5 g. of ethyl 4-aminobenzoate, 34.9 g. of 3-(p-chlorophenyl)propanol O-mesylate in 100 ml. of hexamethylphosphoramide is heated at 125°-130° C. for 16 hours. The solution is diluted with 50 ml. of tetrahydrofuran and with 150 ml. of water. Chilling and filtering gives crystals which are washed with water and recrystallized from ethanol to give 28.3 g. of light yellow crystals. Recrystallizations give the product as crystals, m.p. 122°-124° C.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:31][CH3:32])=[C:16]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[N:26][CH:27]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[N:26][C:25]([N:28]([CH3:30])[CH3:29])=[N:24][CH:23]=2)[C:15]([O:31][CH3:32])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.20 mmol), 5-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyrimidin-2-amine (60 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.37 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H24ClN8O (M+H)+: m/z=439.2. found: 439.1. 1H NMR (DMSO-d6, 400 MHz) δ 12.91 (1H, br s), 8.29 (2H, s), 8.20 (1H, m), 8.13 (1H, s), 8.10 (1H, s), 7.61 (1H, s), 5.73 (1H, m), 3.46 (3H, s), 3.16 (6H, s), 2.06 (3H, s), 1.47 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and pyrrolidine according to conditions described in general procedure C. Mp: 111-113° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58 (s, 6 H), 1.81 (bs, 4 H), 3.03-3.40 (m, 8 H), 6.15 (d, J=5.5, 1 H), 6.95 (d, 1 H), 7.15 (d, 1 H), 7.40 (d, J=8.4 Hz,1 H), 7.46 (s, 1 H), 7.50-7.60 (m, 3 H), 7.82-7.86 (m, 1 H), 7.97-7.99 (m, 1 H), 8.21-8.23 (m, 1 H), 10.43 (s, 1 H).
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])=[CH:11][C:9]=2[CH:10]=1.Br[C:25]1[CH:26]=[CH:27][C:28]2[S:34](=[O:36])(=[O:35])[CH2:33][CH2:32][C:31]([C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:54])[CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:42][CH:41]=3)=[O:38])=[CH:30][C:29]=2[CH:55]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:54][N:47]([CH2:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([C:31]2[CH2:32][CH2:33][S:34](=[O:36])(=[O:35])[C:28]3[CH:27]=[CH:26][C:25]([C:6]4[O:7][C:8]5[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])=[CH:11][C:9]=5[CH:10]=4)=[CH:55][C:29]=3[CH:30]=2)=[O:38])=[CH:41][CH:42]=1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: CCCOCCOc1ccc2oc(OB([O-])[O-])cc2c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOCCOc1ccc2oc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)cc2c1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 5-propoxyethoxy-benzofuran-2-yl borate (198 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(5-propoxyethoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 140) (200 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:25])[CH:9]=[C:10]([CH:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(Br)c3c(N)ncnn23)CC1
Temperature: -20 °C
Reaction time: 4 h
Yield: 195.4 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)azepane-1-carboxylate (1.44 g, 4.35 mmol) in tetrahydrofuran (22 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (621 mg, 2.17 mmol) in 4 portions over 15 min. The mixture was allowed to stir (−20° C.) for 4 h. The reaction was quenched with the addition 5% aqueous K2CO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 5% aqueous K2CO3 (25 mL), brine, dried (Na2SO4) and evaporated to provide 1.74 g (98%) of the desired product, which contained trace impurities. ES-MS m/z 411.91 [M+H]+, HPLC RT (min) 2.92.
Reaction SMILES: OC(C1N=CC([C:11]2[S:15][C:14]([N+:16]([O-:18])=[O:17])=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=CC=1)(C)C.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:37]=[N:38][N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=3)=[CH:32][CH:31]=2)O1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>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>[N+:16]([C:14]1[S:15][C:11]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[N:37]=[N:38][N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:47])[CH3:48])[CH:40]=3)=[CH:34][CH:35]=2)=[CH:12][C:13]=1[C:19]([NH2:21])=[O:20])([O-:18])=[O:17]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Reactant: CC1(C)OB(c2ccc(-c3cn(COCC[Si](C)(C)C)nn3)cc2)OC1(C)C
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: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(-c3cc(C(N)=O)c([N+](=O)[O-])s3)cc2)nn1
Temperature: 90 °C

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (470 mg, 1.87 mmol), 4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazole (751 mg, 1.87 mmol), and Pd(PPh3)4 (108 mg, 0.094 mmol) were combined in a vial and evacuated/backfilled with nitrogen. THF (4.4 mL) and 2 N Na2CO3 (1.9 mL) were added. The reaction mixture was heated to 90° C. overnight. The black reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, combined with silica, and evaporated. Flash chromatography (dry load, 50-100% EtOAc/hexanes) afforded a brown solid that was triturated with CH2Cl2 and filtered to isolate the title compound as a yellow solid. The mother liquor was concentrated, triturated again, and filtered to isolate an additional batch of the title compound.
Reaction SMILES: Cl.[OH:2][NH:3][C:4]([C@H:6]1[C:11]([CH3:13])([CH3:12])[S:10][CH2:9][CH2:8][N:7]1[S:14]([C:17]1[CH:37]=[CH:36][C:20]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5]>ClCCl.CO>[NH2:28][CH2:27][CH2:26][CH2:25][C:24]#[C:23][CH2:22][O:21][C:20]1[CH:36]=[CH:37][C:17]([S:14]([N:7]2[CH2:8][CH2:9][S:10][C:11]([CH3:12])([CH3:13])[C@@H:6]2[C:4]([NH:3][OH:2])=[O:5])(=[O:15])=[O:16])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)NO)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCCN)cc2)[C@H]1C(=O)NO
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of 0.104 g (0.192 mmol) of tert-butyl 6-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfonyl)-phenoxy]-4-hexynylcarbamate in 6 mL of dichloro-methane and 2 mL of methanol for 5 min, and the reaction was stoppered and let stand for 1 h and then concentrated in vacuo. The residue was triturated with ether to provide 0.092 g (100%) of (3S)-4-({4-[(6-amino-2-hexynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide as a cream solid. Electrospray Mass Spec: 442.1 (M+H)+
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13](N)=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2].N([O-])=[O:18].[Na+]>Cl>[C:1]([N:4]1[CH2:9][CH:8]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:18])=[CH:12][CH:11]=3)([CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC2CC2(c2ccc(N)cc2)C1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CC(=O)N1CC2CC2(c2ccc(O)cc2)C1

Procedure:
A solution of 3-acetyl-1-(p-aminophenyl)-3-azabicyclo[3.1.0]hexane in 8N hydrochloric acid is diazotized at 0° C, with aqueous sodium nitrite. The solution is then allowed to stand at ambient temperature until the evolution of nitrogen ceases. This mixture is then extracted with ether, and the extract is dried over sodium sulfate, filtered and then evaporated under reduced pressure to give 3-acetyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [H-].[Na+].C(O)CO.[S:7](Cl)(=[O:10])(=[O:9])[NH2:8].S(O[CH2:17][CH2:18][O:19][S:20](=[O:23])(=[O:22])[NH2:21])(=O)(=O)N.[CH2:24]([OH:30])[CH2:25][CH2:26]CCO>COCCOC>[S:7]([O:30][CH2:24][CH2:25][CH2:26][CH2:17][CH2:18][O:19][S:20](=[O:22])(=[O:23])[NH2:21])(=[O:10])(=[O:9])[NH2:8]
Reactant: NS(=O)(=O)OCCOS(N)(=O)=O
Reactant: OCCCCCO
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: OCCO
Product: NS(=O)(=O)OCCCCCOS(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 57% oil dispersion of sodium hydride (8.45 g.; 0.20 mol.) is added to a solution of ethylene glycol (3.1 g.; 0.05 mol.) in 1,2-dimethoxyethane (100 ml.). The resulting suspension is stirred at room temperature for 2 hours and then cooled to +4° C. Sulfamoyl chloride (20.79 g.; 0.18 mol.) is dissolved in 1,2-dimethoxyethane (400 ml.) and added dropwise to the solution with stirring. The reaction mixture is stirred at +4° C for an additional 24 hours. A precipitate forms which is filtered off and the filtrate is concentrated. The residue is partitioned between heptane and methanol, and the methanol solution is concentrated to a syrup which crystallizes from ethyl acetate to yield 6.1 g. (58%) of 1,2-bis-O-sulfamyl-1,2-ethanediol, m.p. 96.5°-99° C. When in the above procedure 1,5-pentanediol is employed in place of ethylene glycol, 1,5-bis-O-sulfamyl-1,5-pentanediol is obtained.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][OH:6].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:11])([F:1])[C:7]([F:8])([F:9])[F:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: OCCCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A mixture of 4,4,5,5,5-pentafluoropentan-1-ol (1 g, 5.6 mmol), p-toluenesulfonylchloride (1.3 g, 6.8 mmol), and triethylamine (1.2 mL, 8.4 mmol) in DCM (20 mL) was stirred at room temperature for 18 h. Water was added to the reaction mixture, the two layers were separated, and the aqueous layer was extracted with DCM (2×). The organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to afford 1.7 g of 4,4,5,5,5-pentafluoropentyl 4-methylbenzenesulfonate as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9](B(O)O)[C:2]1=2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.O=[CH:22][C:23]([OH:25])=[O:24]>CC#N>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:22]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:23]([OH:25])=[O:24])[C:2]1=2
Reactant: O=CC(=O)O
Reactant: Nc1ccccc1
Reactant: OB(O)c1cccc2ccsc12
Solvent: O
Solvent: CC#N
Product: O=C(O)C(Nc1ccccc1)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A mixture of benzo[b]thiophen-7-ylboronic acid (300 mg, 1.68 mmol), aniline (157 mg, 1.68 mmol), and 2-oxoacetic acid hydrate (155 mg, 1.68 mmol) in CH3CN (20 ml) was stirred at room temperature for 2 hours. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain 2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetic acid (303 mg, 63.5% yield).
Reaction SMILES: BrBr.[CH3:3][NH:4][C:5](=[S:16])[NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]>C(O)(=O)C>[CH3:3][NH:4][C:5]1[S:16][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][C:7]=2[N:6]=1
Reactant: CNC(=S)Nc1cccc(C(=O)O)c1
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1nc2cccc(C(=O)O)c2s1
Temperature: 95 °C
Yield: 85.3 %

Procedure:
A solution of 163 g of bromine and 50 g of 100% acetic acid is added dropwise to a suspension of 212 g of 3-(N′-methylthioureido)-benzoic acid and 500 g of 100% acetic acid at 45-50° C. in the course of 2 hours. The mixture is then heated to 90-100° C. in the course of 2.5 hours and is allowed to react for a further 2 hours until the release of the gas has ended. After 150 g of acetic acid have been distilled off at 80-85° C. under reduced pressure, 200 g of water are added and the mixture is brought to pH 2 by dropwise addition of 30% sodium hydroxide solution. Filtration with suction at 70-80° C. and washing with water gives 179.2 g of the title compound of melting point: >330° C. HPLC analysis shows a content of 94.6% of the title compound, in addition to 3-4% of isomeric 2-methylamino-benzothiazole-5-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH:33]1([N:39]=[C:40]=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:40]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:41])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: O=C(Nc1ccc(-n2cnc3c(NC(=O)NC4CCCCC4)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and cyclohexyl isocyanate by using the same techniques as in Example 119.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([Cl:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>>[ClH:32].[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cc(C(F)(F)F)ccc32)cc1

Procedure:
(22.2 mg, 69%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-methoxyphenylsulfonyl chloride (22.1 mg, 0.107 mmol). HRMS-FAB+ for C22H21N2O3SF3.HCl, calculated MH+ : 451.13031; found: 451.13007.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[CH:7][N:8]=[C:9]3[C:14]=2[C:13](=O)[CH2:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:18][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]3[CH3:1])[CH:13]=[CH:12][CH:11]=[CH:10]2
Reactant: Cc1cccc2cnc3c(c12)C(=O)CC=C3
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c(Cl)nc3ccccc3c12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
The above compound, 10-methyl-phenanthridinone (4.0 grams, 19 mmole) was added to a reaction flask containing phosphorus pentachloride (6.0 grams, 0.29 mole) and phosphoryl chloride (50 mL). The reaction mixture was refluxed for 4 hours, cooled to room temperature and diluted with toluene. The excess phosphoryl chloride and toluene were removed by a rotary evaporator. The residue was dissolved into ethyl acetate and washed with distilled water followed by brine. The solvent layer was dried over magnesium sulfate, filtered and concentrated to give 6-chloro-10-methylphenanthridine (4.1 grams, 95%) as an off-white solid. The product was confirmed by Mass Spec and NMR and not purified further but used directly in the next step.