Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[CH2:33][CH2:34][NH2:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:35][CH2:34][CH2:33][C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=4)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cccc(F)c1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 68 was coupled with 3-fluorophenethylamine following procedure F. LC-MS showed the product had the expected M+H+ of 506. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (m, 2H) 8.0 (m, 1H) 7.7 (m, 1H) 7.5 (m, 2H) 7.0 (m, 4H) 5.3 (m, 1H) 3.9 (m, 4H) 3.7 (m, 4H) 3.0 (m, 4H) 1.6 (m, 3H) 1.4 (s, 9H).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=2[F:37])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:39]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:39].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=1[F:37]
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Reactant: Fc1cc(Br)ccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1C(F)(F)F
Agent: Cl
Product: Fc1cc(Br)ccc1C(OC1CNC1)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydryloxy]azetidine (113) (15 mmol) using the procedure described for compound (9) (2.26 g, 51%).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:10]2[C:14](=[O:15])[CH:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[S:12][C:11]2=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:40]1[CH:41]=[C:42]([C:47]#[C:48][CH2:49]Br)[CH:43]=[C:44](F)[CH:45]=1.[NH4+].[Cl-:52]>CN(C=O)C.O>[C:33]1([C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:10]2[C:14](=[O:15])[C:13]([CH2:49][C:48]#[C:47][C:42]3[CH:43]=[CH:44][C:45]([Cl:52])=[CH:40][CH:41]=3)([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[S:12][C:11]2=[O:26])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)C2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reactant: Fc1cc(F)cc(C#CCBr)c1
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Sodium hydride (80% dispersion in mineral oil, 93 mg, 3.10 mmol) was added to a solution of N-(triphenylmethyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [(VI), from Example 34, 1.06 g, 2.07 mmol) in dry DMF (9 mL) at 0° C. under a dry N2 atmosphere. After 20 min, [3-(4-chlorophenyl)-prop-2-ynyl]-bromide [(IX), from Example 21, 0.52 g, 2.27 mmol] was added and the reaction mixture was stirred an additional 20 min at 0° C. Saturated aqueous NH4Cl (60 mL) was added, followed by water (60 mL). After stirring for 10 min, the solid was filtered, washed with water and triturated with petroleum ether to provide the title compound as a grey solid (1.16 g, 90%): mp 221°-223° C.; NMR (CDCl3): δ7.80 (d, J=8.2 Hz, 2H, ArH), 7.45 (d, J=7.5 Hz, 6H, CPh3H), 7.35 (d, J=8.2 Hz, 2H, ArH), 7.14 (m, 11H, Ar'H, CPh3H), 6.98 (d, J=8.5 Hz, 2H, Ar'H), 3.29 (d, J=16.7 Hz, 1H, CH2), 3.12 (d, J=16.7 Hz, 1H, CH2), 2.46 (s, 3H, CH3).
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[CH:18]1([CH2:23][CH2:24][C:25](Cl)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>ClC(Cl)C>[CH:18]1([CH2:23][CH2:24][C:25]([NH:10][C:9]2[CH:1]=[C:2]3[C:6]4=[C:7]([CH2:11][CH2:12][N:5]4[C:4]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:3]3=4)[CH:8]=2)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Reactant: O=C(Cl)CCC1CCCC1
Solvent: CC(Cl)Cl
Product: O=C(CCC1CCCC1)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 6.5 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), 3-cyclopentylpropionyl chloride (0.068 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 3-cyclopentyl-N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-ylpropanamide (10 mg). MS (ESI) m/z 351; HPLC purity 100% at 210-370 nm, 11.4 min.; 100% at 250 nm, 11.4 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H30N2O+H+, 351.24309; found (ESI, [M+H]+), 351.2423.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=O)[C:5]([CH3:17])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH:9]([CH3:14])[CH2:8][CH:7]2[O:15][CH3:16].[CH2:21]([N:23]1[C:27]([OH:28])=[CH:26][CH:25]=[N:24]1)[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:3]=[C:4]([C:18]([C:26]2[CH:25]=[N:24][N:23]([CH2:21][CH3:22])[C:27]=2[OH:28])=[O:20])[C:5]([CH3:17])=[C:6]2[C:11]=1[S:10](=[O:12])(=[O:13])[CH:9]([CH3:14])[CH2:8][CH:7]2[O:15][CH3:16]
Reactant: CCn1nccc1O
Reactant: COC1CC(C)S(=O)(=O)c2c(F)cc(C(=O)O)c(C)c21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2cc(F)c3c(c2C)C(OC)CC(C)S3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
In a 50-ml flask, 0.70 g (0.0023 mol) of 8-fluoro-4-methoxy-2,5-dimethylthiochroman-6-carboxylic acid-1,1-dioxide, 0.28 g (0.0025 mol) of 1-ethyl-5-hydroxypyrazole and 0.52 g (0.0025 mol) of DCC (N,N'-dicyclohexylcarbodiimide) were added to 5 ml of tert-amyl alcohol at the same time, and the mixture was stirred at room temperature for 30 minutes. Then, 0.17 g (0.00125 mol) of anhydrous potassium carbonate was added. The reaction mixture was allowed to react at 80° C. for 8 hours, and then the reaction solvent was distilled off under reduced pressure. The remainder was dispersed in a 2% potassium carbonate aqueous solution and ethyl acetate to separate it into two phases. Further, the aqueous phase was acidified with 5% hydrochloric acid. and the precipitated oil was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 0.70 g of 8-fluoro-4-methoxy-2,5-dimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound 40) shown in Table 5. The yield thereof was 78%.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[OH-].[Na+]>O>[N:11]1[C:1](=[O:2])[N:12]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: O=C(Cl)Cl
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1N=c2ccccc2=N1
Yield: 94 %

Procedure:
100 g (1.01 mol) of phosgene are passed into 108 g (1 mol) of o-phenylenediamine in 800 ml of water at 80° C. over a period of 4 hours and the pH is kept constant at 6.5 by simultaneous metering in of 231 g (1.9 mol) of 50% strength aqueous sodium hydroxide solution. After filtration with suction and washing with water, 126 g of benzimidazol-2-one are obtained, which corresponds to a yield of 94% of theory.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[C:26](Br)[CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:37][N:38](C)C=O.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[C:26]([C:37]#[N:38])[CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CN(C)C=O
Reactant: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(Br)c3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(C#N)c3)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of this 3-bromo-4-(2'-methylbutyl)benzoic acid 4-octyloxy-4'-biphenylyl ester (5.5 g, 0.01 mol), cuprous cyanide (1.1 g, 0.06 mol) and dimethylformamide (20 ml) was heated to 145°-147° C., following by agitating it for 6 hours, adding a mixture of ferric chloride (4 g), hydrochloric acid (1 ml) and water (7 ml), keeping the mixture at 60°-70° C. for 15 minutes, feeding it into ice water, adding toluene, sufficiently agitating the mixture, transferring it into a separating funnel, several times washing the resulting organic layer with water, drying it over anhydrous MgSO4, distilling off toluene and recrystallizing the residue from ethanol (50 ml) to obtain the objective 3-cyano-4-(2'-methylbutyl)benzoic acid 4'-octyloxy-4-biphenylyl ester (1.7 g). The phase transition points of this product were as follows: ##STR46##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(O)(=O)C.[CH2:13](OC(OCC)OCC)C.[N-:23]=[N+:24]=[N-:25].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[N:25][N:24]=[N:23]2)=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(-n2cnnn2)nc1
Temperature: 80 °C

Procedure:
To a mixture of 5-bromopyridin-2-amine (5.0 g, 28.9 mmol) in acetic acid (40 ml, 699 mmol) was added (diethoxymethoxy) ethane (7.70 ml, 46.2 mmol), followed by sodium azide (2.82 g, 43.3 mmol). The mixture was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected and dried under high vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH:20]S(O)(=O)=O>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C#N)c1N
Reactant: O=S(=O)(O)O
Product: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Part C: A mixture of 1.5 g (5.5 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole in 5 mL conc. H2SO4 was stirred at room temperature for 24 hours. The reaction was slowly quenched with ice and then diluted with water. The solution was made basic with saturated Na2CO3, stirred 2 h and filtered. The solid was recrystallized from hexanes/EtOAc to afford 847 mg (53%) of 5-amino-3-isopropyl-1-(2-chloro-6-methylphenyl) pyrazole-4-carboxamide, mp 72-74° C. Mass Spec. (ES−): 291 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)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>[C:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Reactant: OB(O)c1ccccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=c1ccn2nc(-c3ccccc3-c3ccccc3)ccc2c1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 g, 0.17 mmol), biphenyl-2-ylboronic acid (51.4 mg, 0.26 mmol), and Tetrakis (19.6 g, 0.017 mmol) were added to a flask and purged with N2 (3×). After the addition of toluene (5 mL), ethanol (0.5 mL), and 2M Na2CO3 (0.5 mL) the resulting mixture was heated to 90° C. for 1 hour. The reaction was concentrated in vacuo and the crude residue was dissolved in H2O/EtOAc (1:1) and extracted with H2O, 1N HCl (2×), brine (2×), dried over MgSO4, and concentrated in vacuo to yield an oil. The crude material was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH) to yield the title compound.
Reaction SMILES: [N:1]([O-:3])=[O:2].[K+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]=1.N>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C1=NCCc2ccccc21
Reactant: O=N[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
15 g of potassium nitrite was added to a concentrated sulfuric acid (70 ml) solution containing 18 g (0.14 mol) of 3,4-dihydroisoquinoline was added thereto at −15° C. over 20 minutes. After stirring at room temperature for one hour, the mixture was heated at 60° C. for 40 minutes. The reaction solution was poured into ice-water and basified with an aqueous ammonia. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over magnesium sulfate. After concentrating, decaline (100 ml), nitrobenzene (100 ml) and 2 g of Pd-Black were added to the residue, and the mixture was heated at 200° C. overnight in nitrogen stream. The reaction solution was washed with ethyl acetate and then extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate and then an aqueous sodium hydroxide was added thereto. The resulting precipitates were collected by filtration and washed with water, to give 14.4 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C1(CNCC2CCCCC2)CCCCC1.[C:27]([NH:35][C:36]1[CH:48]=[C:47]([CH:49]=[CH2:50])[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C(=O)C>[C:27]([NH:35][C:36]1[CH:48]=[C:47](/[CH:49]=[CH:50]/[C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc3c(c2)NC(=O)C3)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 7 h
Yield: 35 %

Procedure:
0.20 g of 6-bromo-2-oxoindoline, 0.40 mL of N,N-dicyclohexylmethylamine and 18 mg of trans-di(μ-acetato)bis-o-(di-o-tolylphosphino)benzyl dipalladium(II) were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.46 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 7 hours. After the reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; hexane:ethyl acetate=1:1] to obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-(2-oxoindolin-6-yl)vinyl)benzoate as green solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)[NH:4][N:3]=1.Cl.[CH:31]1([C:34]2([OH:38])[CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>CCCCO.CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12]([N:36]3[CH2:37][C:34]([CH:31]4[CH2:33][CH2:32]4)([OH:38])[CH2:35]3)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)[NH:4][N:3]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CCCC4)cc3)n2)[nH]n1
Reactant: OC1(C2CC2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(N3CC(O)(C4CC4)C3)nc(Sc3ccc(NC(=O)C4CCCC4)cc3)n2)[nH]n1
Temperature: 100 °C

Procedure:
To a suspension of N-(4-(4-(3-methyl-1H-pyrazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopentanecarboxamide (200 mg, 0.47 mmol) and 3-cyclopropyl azetidin-3-ol hydrochloride (70 mg, 0.47 mmol) in n-BuOH (5 ml) was added diisopropylethylamine (239 mg, 1.88 mmol, 0.30 ml). The mixture was heated to 100° C. for 16 hrs and then allowed to cool to room temperature and diluted with EtOAc (30 ml) and sat NaHCO-3. The organic layer was washed with brine, dried (Na2SO4) and concentrated. Crude product was then purified by flash chromatography EtOAc 5% MeOH:EtOAc to give title compound as an off white solid (70 mg, 30%). 1H NMR (DMSO-d6) 0.30-0.35 (2H, m), 0.39-0.44 (2H, m), 1.16-1.21 (1H, m), 1.56-1.75 (6H, m), 1.83-1.90 (2H, m), 2.00 (3H, s), 2.76-2.82 (1H, m), 3.65 (4H, dd), 5.35 (1H, s), 5.58 (1H, s), 7.47 (2H, d), 7.72 (2H, d), 9.19 (1H, s), 10.06 (1H, s), 11.65 (1H, s). ES+ 506.
Reaction SMILES: COC1C(OC)=NS(=O)(=O)N=1.[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[C:13]([NH2:15])=[NH:14].N(C1OC=C(CCC[CH2:38][NH:39][C:40]2(OC)[NH:44][S:43](=[O:46])(=[O:45])[N:42]=[CH:41]2)N=1)C(N)=N.CN>>[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:40]2([NH:39][CH3:38])[NH:44][S:43](=[O:46])(=[O:45])[N:42]=[CH:41]2)[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)Nc1nc(CCCCN)co1
Reactant: COC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1

Procedure:
When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 4-[(2-guanidino-4-oxazolyl]butylamine [prepared according to the procedure described in Belgian Pat. No. 866,155] and the resultant 3-{4-[(2-guanidino-4-oxazolyl]butylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with excess methylamine, the title compound is thereby produced.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].Br[CH2:26][C:27]#[C:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][C:27]#[C:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: BrCC#Cc1ccc(OCCCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCC#Cc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(3-bromoprop-1-yn-1-yl)-4-(4-phenoxy-butoxy)benzene.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: BrCC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2c(NCC3CC3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: To the mixture of 3.8 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid, 20 ml of water, 15 ml of ethanol and 2 ml of 4 N aqueous lithium hydroxide, 2.2 g, of cyclopropylmethyl bromide are added while stirring and the pH of the mixture adjusted with lithium hydroxide to 7.0 during 24 hours. Thereupon, it is filtered, the filtrate diluted with water, washed with diethyl ether and acidified with concentrated hydrochloric acid. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-cyclopropylmethylamino-5-sulfamoylbenzoic acid melting at 200°-204°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:24]([NH:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1sc(NC(=O)c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred cold mixture of ethyl 2-amino-4-phenylthiazole-5-carboxylate (1.24 g, 5.00 mmol), 4-dimethylaminopyridine (0.10 g, 16 mol %) and pyridine (4.0 mL, 10 equiv) in dichloromethane (20.0 mL) was added benzoyl chloride (0.70 g, 5.00 mmol) in dichloromethane (3 mL). The mixture was stirred at ambient temperature for 2 h, then washed with 5% hydrochloric acid solution, water, and dried over anhydrous sodium sulfate. Removal of the solvent afforded the title compound in 92% yield (1.62 g); 1H NMR (CDCl3, 300 MHz) δ 10.10 (s, 1H), 8.15 (d, J=7.2 Hz, 2H), 7.85-7.45 (m, 8H), 4.24 (q, J=5.9 Hz, 2H), 1.19 (t, J=5.9 Hz, 3H); MS (ES+) m/z 353.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18]>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9]
Reactant: Fc1cc(Br)ccc1I
Reactant: Fc1ccc(S)c(Br)c1
Product: Fc1ccc(Sc2ccc(Br)cc2F)c(Br)c1

Procedure:
Prepared from 4-bromo-2-fluoro-1-iodo-benzene and 2-bromo-4-fluoro-benzenethiol.