Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]4[CH2:37][CH3:38])[N:18]=[C:19]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:20]=3[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)sc2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)sc2n1
Reaction time: 2 h

Procedure:
To a solution of 3-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (493 g, 0.92 mmol) in AcOH (20 mL) was added 10% Pd(OH)2/C (200 mg) and the resulting mixture stirred under an atmosphere of H2 for 2 h. The reaction mixture was filtered through Celite®, washing with EtOAc. The filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([N:42]=[C:43]=[O:44])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>N1C=CC=CC=1>[F:30][C:31]([F:45])([F:46])[C:32]1[CH:33]=[C:34]([NH:42][C:43](=[O:44])[NH:1][C:2]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:3]=2[O:4][C:5]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2N)c(C(=O)O)c1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)O)c1

Procedure:
2-(2-amino-4-trifluoromethyphenoxy)-5-(1,1,3,3-tetramethylbutyl)benzoic acid (140 mg, 0.0003 mol) and 3,5-di(trifluoromethyl)phenyl isocyanate (86 μl, 0.0005 mol) were mixed in pyridine (8 ml) at room temperature 16 h. The solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to yield the title compound; mp 233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12]CC)[CH3:11].Cl>C(O)C>[ClH:1].[CH2:10]([O:12][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCOCC
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
10 g of 4-chlorobenzonitrile was suspended in 12 ml of ethanol and dissolved by adding diethyl ether. While being cooled in an ice bath, it was saturated with HCl gas. After 72 hours, precipitated product was suctioned out. The product was washed with diethyl ether.
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:30][C:23]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:3]1([O:7][CH2:8][C@H:9]([O:20][C:22]2[N:27]=[CH:26][N:25]=[C:24]3[N:28]([C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)[N:29]=[CH:30][C:23]=23)[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ncccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2cccnc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
Sodium hydride (19.54 mg, 0.49 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (102 mg, 0.41 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate V5) (100 mg, 0.41 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (78 mg, 41.6%). 1H NMR (400 MHz, DMSO) δ 1.23-1.36 (m, 1H), 1.38-1.51 (m, 1H), 1.60-1.75 (m, 2H), 1.96-2.07 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.71-3.87 (m, 2H), 3.89-3.98 (m, 1H), 5.71-5.78 (m, 1H), 7.28-7.34 (m, 1H), 7.75 (d, 1H), 8.15 (s, 1H), 8.39 (s, 1H), 8.45-8.51 (m, 2H), 8.93 (s, 1H), 11.01 (s, 1H), m/z (ESI+) (M+H)+=461.48; HPLC tR=1.75 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:24]([C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C2NCCc3ccsc32)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
was prepared from 7-(4-methoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin (80 mg) in toluene (10 ml), 4-methoxybenzoyl chloride (66.5 mg) and triethylamine (90 uL) as described in example 2. Yield 80% of the title compound, MS: M+=379.
Reaction SMILES: [OH-].[Na+].[Cl:3]Cl.Cl[O-].[Na+].[OH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>>[Cl:3][C:15]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:8])=[N:17][CH:16]=1
Reactant: ClCl
Reactant: O=C(O)c1cccnc1O
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cnc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide, 336 g of 50% solution (4.2 mole) in 1 kg of ice was treated with bubbling chlorine gas while stirring until 78 g (1.1 mole) of chlorine was taken into the solution. To the resulting cold, basic sodium hypochlorite solution was added 142 g (1.0 mole) of 2-hydroxynicotinic acid in one portion. Within 1/2 hr the temperature had risen to 35° C. and dissolution had occurred. The mixture was stirred overnight after which time 13CNMR analysis indicated the ratio of starting material to desired product (as the disodium salt) was about 30:70%. Another solution of basic sodium hypochlorite was prepared by the above procedure by absorbing 35 g (0.5 mole) of chlorine gas in a mixture of 100 g of 50% solution (1.25 mole) of sodium hydroxide and 278 g of ice. This hypochlorite solution was added to the main reaction mixture and stirring was continued overnight. 13CNMR analysis indicated the starting 2-hydroxynicotinic acid had all reacted and the desired 5-chloro-2-hydroxynicotinic acid was present as the disodium salt. Sodium bisulfite, 14 g was added and stirring was continued for 1.5 hr. The reaction mixture was gradually added to a cooled, stirred solution of 337 ml of concentrated (37%) hydrochloric acid. The maximum temperature of the acidified mixture was 25° C. The yield of title compound on separation and drying was 146 g (84%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[NH:13][CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26](Cl)=[O:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:13]([CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19])[C:26](=[O:27])[CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20]
Reactant: Cc1cc2ccccc2c(NC2CCOC2=O)c1C
Reactant: COCCOCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCOCC(=O)N(c1c(C)c(C)cc2ccccc12)C1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 15.3 g of N-(2,3-dimethylnaphtyl)-N-(2-oxo-tetrahydrofuran-3-yl)-amine in 120 ml of toluene are added dropwise 12.2 g of 2-methoxyethoxy-acetyl chloride (MAC) in 20 ml of toluene and afterwards 8.1 g of triethylamine in 20 ml of toluene. The temperature of the reaction rises to 35° and is then raised to 40° for 2 hours. There are subsequently added dropwise a further 2 g of MAC and 1.5 g of triethylamine. The temperature is held overnight at 40°, and afterwards a further 2 g of MAC are added dropwise. After 4 hours, the reaction mixture is cooled to room temperature and filtered, and the filtrate is concentrated by evaporation to yield a resinous residue, which is purified through silica gel 60 using ethyl acetate as the eluant. The solid product occurring from the residue is recrystallised from isopropanol with the addition of active charcoal. The resulting product is the colourless diastereoisomeric mixture of the compound No. 32, m.p. 142°-146°.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.N>C(O)C>[CH3:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:22])([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: CSc1nc2nc(C)cc(Cl)n2n1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Agent: N
Solvent: CCO
Product: CSc1nc2nc(C)cc(Nc3ccc(S(F)(F)(F)(F)F)cc3)n2n1
Temperature: 25 °C

Procedure:
To a suspension of 7-chloro-5-methyl-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 8, (0.2 g, 0.932 mmol)), in ethanol (10 mL), 4-aminophenylsulfur pentafluoride (MANCHESTER, 0.204 g, 0.932 mmol) was added and the mixture was stirred at room temperature until reaching completion. Anhydrous ammonia (0.133 mL, 0.932 mmol) was then added to the mixture and solvent was removed in vacuo. The crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures form 95:5 to 40:60%). Upon collection of the appropriate fractions, the title compound was obtained as a light yellow solid.
Reaction SMILES: NC(N)=O.[CH:5]1([NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[OH:22])(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:15]([OH:22])[C:14]=1[S:11]([NH:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)(=[O:13])=[O:12]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 40.2 %

Procedure:
Following the general procedure for urea formation outlined in example 15, (N-cyclopentyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.15 g, 0.52 mmol) and 2,3-dichlorophenylisocyanate(68 μL, 0.52 mmol) were coupled to form the desired urea (0.10 g, 40%). LC-MS m/z 478(M+).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:11].[CH2:23]([O:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29])[CH3:24]>Cl[Pd]Cl>[CH2:23]([O:25][P:26]([C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:11])([O:27][CH2:28][CH3:29])=[O:30])[CH3:24]
Reactant: CCOP(OCC)OCC
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1I
Agent: Cl[Pd]Cl
Product: CCOP(=O)(OCC)c1cc(Br)ccc1NC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a 30 mL vial, 1-(2-iodo-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea (2.00 g, 4.12 mmol) was added along with triethylphosphite (1.03 g, 6.0 mmol) and PdCl2 (49 mg, 0.278 mmol). The vial was flushed with N2 sealed and then heated at 130° C. while stirring overnight. The resulting solution was cooled to room temperature, dissolved in a 1:1 mixture of EtOAc/hexane and then purified on a silica column using mixtures of EtOAc/hexanes to give 1.25 g of 1-(2-diethylphosphono-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[C:48]([NH:51][C:52]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][C:53]=1[C:54](O)=[O:55])(=[O:50])[CH3:49].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[C:58]([Br:61])[CH:59]=[CH:60][C:52]=3[NH:51][C:48](=[O:50])[CH3:49])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1ccc(Br)cc1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(Br)cc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-acetamido-5-bromobenzoic acid (6.0 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1.CO.Cl.[NH2:16][OH:17]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[N:16][OH:17])[CH:5]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 100 ml round flask, 2.31 g (14.1 mmol) of 3-formyl-benzoic acid methyl ester are dissolved in 25 ml of water and 45 ml of methanol and cooled to 0° C. After reaching this temperature, 980 mg (14.1 mmol) of hydroxylamine hydrochloride are added and the mixture stirred for 1 h under warming to room temperature. Then, the mixture is poured onto water and extracted twice with ethyl acetate. The organic layers are dried with brine and over Na2SO4 and concentrated. This yields the title compound as a white solid which is used for the next step without purification. Mass spectrum: m/z (M+H)+: 179.9
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>C(Cl)Cl>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:38])[CH:30]=2)=[O:37])=[CH:15][CH:14]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and N,N-diisopropylethylamine (0.109 mL, 0.63 mmol) in 3.0 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.047 mL, 0.377 mmol) and the reaction stirred at rt for 2 hours. The reaction was quenched with 1.0 mL MeOH, stirred for 15 min and then evaporated. The sample was partitioned between EtOAc and H2O/brine mixture, the EtOAc layer washed with aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4, and evaporated to a tan solid. The solid was chromatographed eluting with CH2Cl2, EtOAc, then 3% MeOH/EtOAc to give the title compound as a white solid (79 mg, 88%). 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.29-7.35 (m, 2H), 7.28 (s, 1H), 7.16-7.23 (m, 2H), 7.10-7.16 (m, 1H), 6.96-7.02 (m, 2H), 6.76 (d, J=7.0 Hz, 1H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.7 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:38]=[CH:37][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH3:36])[CH2:31]3)=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[N+:39]([C:42]1[CH:55]=[CH:54][C:45]([CH2:46][O:47][C:48]([NH:50][C:51](=N)[CH3:52])=[O:49])=[CH:44][CH:43]=1)([O-:41])=[O:40]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:51](=[N:50][C:48]([O:47][CH2:46][C:45]4[CH:54]=[CH:55][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=4)=[O:49])[CH3:52])[C@@H:32]([CH3:36])[CH2:31]3)=[O:29])[CH2:11]2)=[CH:37][CH:38]=1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN[C@@H](C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@@H](C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 30.8 %

Procedure:
2.26 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-methylpiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (i) above] were mixed with 1.14 g of N-(4-nitrobenzyloxycarbonyl)acetamidine and 45 ml of acetonitrile, and the mixture was heated under reflux for 16 hours. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Preparation 1(ii), to give 922 mg of the title compound, as a powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH:4]=[CH2:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]#[N:27])[N:9]=1>C1COCC1>[CH2:3]([O:6][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]#[N:27])[N:9]=1)[CH:4]=[CH2:5]
Reactant: C=CCO
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% in mineral oil, 14 mg) in 2 mL TEF was added 23 uL of allyl alcohol. The mixture was stirred for 15 min at room temp, then 100 mg of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile in 1.5 ml THF was added via cannula. The reaction was heated to 66 C for 16 h, then cooled to room temp, quenched with saturated aqueous NH4Cl, and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic solution was washed once with brine, then dried (Na2SO4) and concentrated. Flash chromatography (35 g silica, 3-25% EA/hex) gave a white solid.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH:1]1([CH2:7][C@@H:8]([C:10]([O:12][CH2:17][CH3:18])=[O:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)CC1CCCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
N-[N-[N-(4-(piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-L-β-cyclohexyl alanine, ethyl ester ##STR16##A. β-cyclohexyl alanine (1.5 g) is dissolved in absolute ethanol (75 ml) and the solution cooled to 0° C. Thionyl chloride (1.1 ml) is added dropwise over a period of 10-15 minutes, the solution allowed to warm to room temperature, and then stirred at room temperature for about 18 hours. The reaction mixture is evaporated in vacuo, toluene is azeotroped twice from the residue, and the residue is taken up into ethyl acetate. The ethyl acetate solution is washed with water, 1N sodium hydroxide, water, brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give β-cyclohexyl alanine, ethyl ester.
Reaction SMILES: S(O[CH2:6][CH2:7][O:8][S:9](=[O:12])(=[O:11])[NH2:10])(=O)(=O)N.[CH2:13]([OH:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCO>>[S:9]([O:24][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:6][CH2:7][O:8][S:9](=[O:11])(=[O:12])[NH2:10])(=[O:11])(=[O:8])[NH2:10]
Reactant: NS(=O)(=O)OCCOS(N)(=O)=O
Reactant: OCCCCCCCCCCO
Product: NS(=O)(=O)OCCCCCCCCCCOS(N)(=O)=O

Procedure:
1,10-Bis-O-sulfamyl-1,10-decanediol is prepared in the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in Example 1 except that 1,10-decanediol (67 g., 0.385 mol.) is employed as the alkanediol.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>O1CCCC1>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: Nc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(SCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
Sodium hydride [0.153 g (50% in mineral oil), 3.2 mmol] was added to a solution of 4-aminothiophenol (0.20 g, 1.6 mmol) in 5 ml anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature under nitrogen for 15 min, then 4-trifluoromethylbenzyl chloride (0.236 ml, 1.6 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen. Water (50 ml) was then added and the resulting mixture was extracted with 2×50 ml ethyl acetate. The combined ethyl acetate extracts were washed sequentially with 60 ml saturated aqueous sodium bicarbonate solution, 60 ml water and 60 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The solid residue was purified by flash column chromatography (silica gel, 15 g), eluting with 85:15 hexane/ethyl acetate to yield the title compound as an off-white solid (0.318 g, 70% yield). MS: 284.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C(=O)N([Cl:33])C(=O)C1>C(Cl)Cl>[Cl:33][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:18]=2)[NH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
D5 (300 mg) and NCS (113 mg) were dissolved in DCM (4.2 ml) and stirred overnight at room temperature. The reaction mixture was then diluted with DCM and washed with H2O. The aqueous solution was extracted with two further portions of DCM and the combined organic solutions were evaporated to dryness. The crude product was triturated with methanol to give the title compound (42 mg) as a brown solid. The methanol was then evaporated and the resultant brown solid triturated with DCM to give a second batch of the title compound (205 mg) as a brown solid. δH (d6-DMSO, 400 MHz): 1.37 (6H, d), 4.89 (1H, septet), 7.45 (1H, d), 7.62 (1H, d), 7.70 (1H, s), 7.93 (1H, d), 8.15 (1H, d), 8.24 (1H, s), 8.25 (1H, s), 11.77 (1H, s). MS (ES): C19H1535Cl2N3O2 requires 387; found 388 (MH+).