Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:37][CH2:36][C:31]4(OCC[O:32]4)[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:40])[F:41])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:27])[N:28]3[CH2:29][CH2:30][C:31](=[O:32])[CH2:36][CH2:37]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CC(=O)N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide (46.7 g, 79.5 mmol) in dioxane (280 mL) was cooled in an ice bath before being treated with concentrated hydrochloric acid (210 mL) at a rate which maintained an internal temperature below 22° C. On complete addition, the reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction was cooled in an ice bath, diluted with ethyl acetate and water and the pH of the aqueous phase adjusted to ˜8 by the portionwise addition of solid Na2CO3. The mixture was extracted with ethyl acetate (×4) and the combined organic extract was dried (Na2CO3) and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-pyrazol-4-yl}-amide.dioxane as a beige solid (48.8 g, 97%). LCMS (Method 3) [M+H]+=544.2, RT=2.85 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.87 (s, 1H), 8.79 (dd, 1H, J=1.8, 7.0 Hz), 8.70 (s, 1H), 8.57 (dd, 1H, J=1.8, 4.0 Hz), 8.47 (s, 1H), 7.67 (d, 1H, J=2.8 Hz), 7.43 (dd, 1H, J=2.7, 8.7 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.01 (dd, 1H, J=4.3, 7.0 Hz), 6.48 (t, 1H, J=74.0 Hz), 5.14 (s, 2H), 3.93 (t, 2H, J=6.2 Hz), 3.85 (t, 2H, J=6.2 Hz), 3.70 (s, 8H), 2.50 (t, 2H, J=6.2 Hz), 2.42 (t, 2H, J=6.1 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC.O>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: Fc1c(Br)ccc2c1CCC(=S)N2
Reactant: CC(=O)NN
Solvent: CCCCO
Solvent: O
Product: Cc1nnc2n1-c1ccc(Br)c(F)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution 6-bromo-5-fluoro-3,4-dihydroquinoline-2(1H)-thione (146-6; 0.25 g, 0.00096 mol) in n-butanol (10 mL) was added acetic hydrazide (0.177 g, 0.0024 mol). Reaction mass was heated at 120° C. and maintained for overnight. The reaction mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO) δ 7.755-7.714 (t, J=8.4 Hz, 1H), 7.487-7.462 (dd, J=1.2 Hz, 1H), 3.034-3.008 (d, J=10.4 Hz, 4H), 2.640 (s, 3H) MS (M+1): 284.0.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[O:19])=O)C1C=CC=CC=1.[N:26]1[C:35]2[C:30](=[N:31][C:32]([CH:36]=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.N1CCCCC1>CC(O)C>[N:31]1[C:30]2[C:35](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:34]=[CH:33][C:32]=1[CH:36]=[C:15]1[NH:11][C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[O:19])=[N:13][C:14]1=[O:16]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: Cc1ccsc1C(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: Cc1ccsc1C(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To a mixture of 2-[(3-methyl-thiophene-2-carbonyl)-amino]-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (42.0 mg, 0.12 mmol), 1,5-naphthyridine-6-carboxaldehyde (18.6 mg, 0.12 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give 3-methyl-thiophene-2-carboxylic acid (5-[1,5]naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-amide as a light yellow solid (13.3 mg, 30.5%). HR-ES (+) m/e calcd. for C18H13N5O2S: (M+H)+ 364.0863. Found: 364.0862.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][CH2:27][C:28]([F:41])([F:40])[C@:29]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[C:34](Br)[N:33]=3)([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[NH3:42].C(O)CO.CO>C(OCC)(=O)C>[NH2:42][C:34]1[N:33]=[C:32]([C@:29]2([CH3:31])[C:28]([F:41])([F:40])[CH2:27][O:26][C:25]([NH:24][C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:30]2)[C:37]([F:38])=[CH:36][CH:35]=1
Reactant: N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CO
Solvent: OCCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(N)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Reaction time: 43 h
Yield: 25 %

Procedure:
To a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (23.4 g, 28.8 mmol) in ammonia (173 ml, 1.21 mol, 7M in methanol) in a microwave vial was added ethylene glycol (240 ml) and methanol (240 ml). Copper oxide Cu2O (1.21 g, 8.46 mmol) was added and the vial was sealed. The reaction mixture was stirred at 80° C. for 43 hours. The cold reaction mixture was diluted with ethyl acetate and washed with water, aqueous ammonia and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was chromatographed over silica gel (400 g, dichloromethane/methanol 98:2+0.2% ammonia) to give the title compound: 4.29 g (25% yield).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](C(O)=O)=[CH:4][CH:3]=1>[Cu-]=O.CN1CCCC1=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c2c1C(=O)c1ccccc1C2=O
Agent: O=[Cu-]
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Temperature: 150 °C
Yield: 90.5 %

Procedure:
A mixture of 25 parts of 4-chloroanthraquinone-1-carboxylic acid, 180 parts of N-methylpyrrolidone, 4 parts of copper(I) oxide and 3 parts of o-phenanthroline hydrochloride is heated for two hours at 150°C. The mixture is poured onto ice and the precipitate formed is suction filtered. After the filter cake has been dissolved in 100 parts of concentrated sulfuric acid and reprecipitated with 300 parts of water, filtered and dried in vacuo at 80°C there are isolated 19 parts (90.5% of theory) of 1-chloroanthraquinone having a melting point of 156° to 158°C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1ncc(C=O)[nH]1
Yield: 84.8 %

Procedure:
To a suspension of 2-butyl-1H-imidazole-5-methanol (2.02 g) in dry dichloromethane (40 ml) and dry dioxan (60 ml) was added manganese dioxide (7.05 g). The reaction mixture was heated at reflux for 3.5 h before being filtered, and the filtrate concentrated in vacuo to give the title compound as a white solid (1.69 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].I[C:17]1C=CC(C)=CC=1C(O)=O.FC1C=CC(I)=C(C=1)C(O)=O>>[CH3:17][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1I
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting for 2-iodo-5-methyl benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.87 (s 2H), 7.66 (d, J=1.3 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.53-7.46 (m, 1H), 2.45 (s, 3H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:27]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc(NCc2ccccc2)cc1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-acetamide dihydrochloride (Example 174) and benzaldehyde according to the method described in Example 177. Melting Point: 147° C. (dec.) (diethylether-ethyl acetate)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[CH:4][CH:3]=1.[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: N#CSCC(=O)c1ccc(F)cc1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2csc(Br)n2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-oxoethyl thiocyanate (3.70 g, 19.0 mmol) in acetic acid (35 ml) was added a 25% hydrogen bromide/acetic acid (35 ml) solution, and the mixture was stirred at 130° C. for 2 hours and at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethanol and water to give the desired product (4.50 g, 91.9%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]#[C:13][C:14]([CH2:18][F:19])([OH:17])[CH2:15][F:16].N1C=CC=CC=1>C(=O)([O-])[O-].[Ba+2].[Pd+2].C(=O)([O-])[O-].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1/[CH:12]=[CH:13]\[C:14]([CH2:18][F:19])([OH:17])[CH2:15][F:16]
Reactant: OC(C#Cc1cc(C(F)(F)F)ccc1Cl)(CF)CF
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: OC(/C=C\c1cc(C(F)(F)F)ccc1Cl)(CF)CF
Temperature: 25 °C
Reaction time: 240 h
Yield: 98.2 %

Procedure:
A mixture of 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-butyn-2-ol (44.5 g), 5% palladium-barium carbonate (6.6 g), pyridine (2.3 g) and ethyl acetate (500 ml) was stirred under a hydrogen atmosphere at room temperature for 10 days. The catalyst was filtered off from the reaction mixture; subsequent concentrating under reduced pressure gave 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-cis-buten-2-ol (44.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)/[CH:7]=[CH:8]/[C:9]([OH:11])=O)([O-:3])=[O:2].[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].C(N(CC)CC)C>S(Cl)(Cl)=O.CN(C)C=O.O1CCOCC1>[CH3:25][O:24][C:15]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])/[CH:8]=[CH:7]/[C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:23]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)/C=C/c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NC(=O)/C=C/c1cccc([N+](=O)[O-])c1

Procedure:
965 mg (5.0 mmol) of trans-3-nitrocinnamic acid are refluxed for 20 minutes in 3 ml of thionyl chloride after the addition of one drop of dimethylformamide. Then the mixture is evaporated to dryness in vacuo and the resulting acid chloride is dissolved in 10 ml of dioxane. This solution is slowly added dropwise, with stirring, at ambient temperature, to a solution of 756 mg (5.0 mmol) of methyl anthranilate and 1.5 ml of triethylamine in 10 ml of dioxane. After one hour the solvent is evaporated off in vacuo, the residue is stirred into about 10 ml of water, then filtered off and the resulting crude product is purified by column chromatography over silica gel (eluant: dichloromethane/petroleum ether=2:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([CH2:35][CH2:36][C:37](=[O:40])[NH:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:43][O:44][C:45]([CH3:61])([CH3:60])[C:46]([NH:48][NH:49][C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=1)=[O:47]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][C:45]([C:46](=[O:47])[NH:48][NH:49][C:50](=[O:59])[C:51]2[CH:56]=[CH:55][C:54]([OH:57])=[C:53]([OH:58])[CH:52]=2)([CH3:60])[CH3:61])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([CH2:35][CH2:36][C:37](=[O:40])[NH:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1nc2nc(CCC(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(CCC(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.5 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-[2-(hydroxycarbamoyl)ethyl]-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (41 mg) (0.66 mmol) and 29 mg of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 1 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours the solvent is removed at room temperature in a high vacuum. The residue is crystallized from ethanol/diethyl ether. The product is filtered off, washed with diethyl ether, water and again with diethyl ether. After drying in a high vacuum at room temperature there are obtained 45 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-[2-(hydroxycarbamoyl)ethyl]-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:14]([O:16]CC)=[O:15])[NH:7]2)#[N:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]([C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[NH:7]2)#[N:2]
Reactant: CCOC(=O)c1cc2c(C#N)cc(C#N)cc2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: O
Product: N#Cc1cc(C#N)c2cc(C(=O)O)[nH]c2c1
Yield: 56.6 %

Procedure:
To a stirred solution of ethyl 4,6-dicyano-1H-indole-2-carboxylate (I-2a: 500 mg, 2.09 mmol) in ethanol (10 mL) was added LiOHH2O (176 mg, 4.18 mmol) and heated to reflux for 6 h. Ethanol was evaporated under reduced pressure and the residue was washed with diethyl ether. The solid formed was dissolved in water (20 mL), acidified with saturated citric acid solution and filtered. The solid was further washed with water and dried under vacuum to afford 250 mg (57%) of 4,6-dicyano-1H-indole-2-carboxylic acid (I-2b) as a light brown solid.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]2[CH:25]=[C:24]([O:23][CH3:22])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Yield: 61.7 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 61.7%, mp: 157-158 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.75 (6H, s, 2×OCH3), 3.77 (3H, s, OCH3), 3.87 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.75 (2H, d, J=8.96 Hz, ArH), 6.92 (2H, s, ArH), 7.23˜7.35 (7H, m, ArH), 11.72 (1H, br, CONH); EI-MS m/e (%): 490.3 (M, 82), 195.1 (100); HREI-MS Calcd. for C27H26N2O5S: 490.1562. found: 490.1560.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[NH:10][N:9]=1)[CH3:2].NC1C2C(=CC=CC=2)NN=1>>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:19]
Reactant: CCN(CC)CCCNc1n[nH]c2ccc(I)cc12
Agent: Nc1n[nH]c2ccccc12
Product: CCN(CC)CCCNc1n[nH]c2ccccc12
Yield: 54 %

Procedure:
The same procedures for preparing 3-(3-diethylaminopropylamino)-5-iodoindazole as described in Example 71 were repeated except that 4.0 g of 3-aminoindazole was employed instead of the 9.7 g of 3-amino-5-iodoindazole. As a result, 4.0 g of 3-(3-diethylaminopropylamino)indazole having the following analytical values was obtained in a yield of 54%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O-:21])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: O=C([O-])C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Yield: 98 %

Procedure:
Sodium 6-[N-(2,4difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (0.48 g) was dissolved in water (100 ml) and adjusted at pH 1 to 2 with 1N HCl and then extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with water (100 ml×2) and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether to obtain 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylic acid (0.44 g) as white powdery crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]=[CH:1]2)=[CH:6][CH:7]=1)=[O:13])[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: O=C(O)c1ccc2ccncc2c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3ccncc3c2)c1
Reaction time: 18 h
Yield: 17.8 %

Procedure:
To a stirred solution of isoquinoline-7-carboxylic acid (200 mg, 1.15 mmol) and N,N-diisopropyl ethylamine (1.20 mL, 6.88 mmol) in methylene chloride (14.0 mL) was added HBTU (438 mg, 1.15 mmol) and the reaction stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (470 mg, 1.15 mmol) was added in one portion and the reaction mixture was stirred under nitrogen for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 0-5% methanol/methylene chloride) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide (100 mg) which was characterized as its bis-HCl salt: mp 142-143° C.; ESI MS m/z 490 [M+H]+
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[NH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (prepared as in Example 12, 200 mg, 0.68 mmol) in methylene chloride (8 mL) was treated with dry N,N-dimethylformamide (1 drop). The reaction mixture was cooled to 0° C. and then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.38 mL, 0.78 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 30 min. The reaction mixture was then treated with N, N-diisopropylethylamine (0.28 mL, 1.64 mmol) followed by a solution of 2-aminoquinoline (208 mg, 1.44 mmol) in dry tetrahydrofuran (1 mL). The resulting reaction mixture was stirred at 25° C. for 17 h. The reaction mixture was concentrated in vacuo. The resulting residue was adsorbed onto silica gel (Merck Silica gel 60, 230-400 mesh) and then purified via Biotage chromatography (FLASH 40S, Silica, 3/2 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-quinolin-2-yl-propionamide (195 mg, 68%) as a white foam; EI-HRMS m/e calcd for C24H26N2O3S (M+) 422.1665, found 422.1664.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][C:7]([NH2:9])=[O:8])([CH3:3])[CH3:2].[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14]N.N>>[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH:9][C:7](=[O:8])[CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)OCCC(N)=O
Reactant: CN(C)CCCN
Agent: N
Product: CC(C)OCCC(=O)NCCCN(C)C

Procedure:
131.2 g (1.0 mole) of 3-isopropoxypropionamide are heated with 1.07.3 g (1.05 mole) of 3-dimethylaminopropylamine for 6 hours in a temperature range of 145°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum 198 g (0.92 mole=91.5% of the theoretical yield) of colorless liquid are obtained having a Bp0.1 of 128°-132° C.