Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:42][CH2:43][CH2:44][N:45]1[CH2:51][CH:50]([OH:52])[C:47]2([CH2:49][CH2:48]2)[CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:52][CH:50]1[C:47]2([CH2:49][CH2:48]2)[CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:20][C:21]([C:23]5[C:24](=[O:36])[N:25]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:26]([CH3:29])[C:27]=5[CH3:28])=[O:22])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][CH:16]=2)[CH2:51]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 40 h
Yield: 72.9 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.413 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (154 mg, 0.619 mmol) and Cs2CO3 (268 mg, 0.826 mmol). The reaction was then stirred at rt for 40 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford a pale yellow solid (192 mg, 73%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2cc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (100 mg) and piperazine (15 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:32][C@H:30]([CH3:31])[CH2:29][NH:28][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: C[C@@H](O)CN
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 37.4 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide (30 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (70 mg), (R)-1-amino-propan-2-ol (70 mg), HBTU (200 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 449.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.44-8.41 (t, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.83-7.80 (d, 1H), 7.71 (s, 2H), 7.54-7.52 (d, 1H), 3.84-3.80 (m, 1H), 3.70 (s, 3H), 3.25-3.22 (m, 2H), 1.10-1.08 (d, 3H), —NH and OH proton signal was not observed.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[N:15][OH:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CC(=NO)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A solution of 7-nitrotetralone (4.20 g, 22.0 mmol) in methanol (100 mL) was cooled to 0° C., and hydroxylamine (1.68 g, 23.2 mmol) and sodium acetate (3.69 g, 46.4 mmol) were added. The reaction was then stirred at room temperature for 12 h. The methanol was evaporated at reduced pressure and dichloromethane (100 mL) was added. The mixture was washed with water, dried over NaSO4 and evaporated at reduced pressure to yield the title compound (4.37 g, 97%). MS (DCI/NH3) m/e 207 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][C:10]([C:18]#[C:19][Si](C)(C)C)=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.C(OCC)(=O)C>[C:18]([C:10]1[N:11]=[C:12]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=2)[N:9]=1)#[CH:19]
Reactant: COc1ccc(Cn2nc(C#C[Si](C)(C)C)nc2N2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.7 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-3-((trimethylsilyl)ethynyl)-1H-1,2,4-triazole (95 mg, 268 μmol, Eq: 1.00) and sodium hydroxide sol. 1N (0.1 ml) in methanol (3 ml) was stirred for 18 hours at 25° C. The mixture was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 3-ethynyl-1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazole (83 mg/110%) as a yellow oil. MS: m/e=283.4 (M+H+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C#N)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.4 g, 0.9 mmol), 4-cyanophenylboronic acid (0.2 g, 1.35 mmol), Na2CO3 (2 M, 2.0 mL), and Pd(PPh3)2Cl2 (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta [a]pentalen-6-yl]-biphenyl-4-carbonitrile as brown solid in 50% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][CH:19](O)[CH3:20]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH:19]([CH3:20])[CH3:18])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)O
Reactant: O=C(O)Cc1ccc(-c2ccccc2)c(F)c1
Product: CC(C)OC(=O)Cc1ccc(-c2ccccc2)c(F)c1

Procedure:
2-propyl (2-fluorobiphenyl-4-yl)acetate (20) was synthesized from 2-(2-fluorobiphenyl-4-yl)acetic acid and 2-propanol according to a similar procedure to step 1 of Example 15. The 1H NMR spectrum of this substance is shown below.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[F:6][C:7]([F:42])([F:41])[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[O:17][CH:18]=[C:19]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]4[CH:37]=[CH:36][N:35]=[C:34]4[CH2:38][CH2:39][NH2:40])=[CH:25][CH:24]=3)[N:20]=2)=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH2:1]([NH:3][C:4]([NH:40][CH2:39][CH2:38][C:34]1[N:33]([CH2:32][CH2:31][CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:19]3[N:20]=[C:16](/[CH:15]=[CH:14]/[C:11]4[CH:10]=[CH:9][C:8]([C:7]([F:42])([F:41])[F:6])=[CH:13][CH:12]=4)[O:17][CH:18]=3)=[CH:24][CH:25]=2)[CH:37]=[CH:36][N:35]=1)=[O:5])[CH3:2]
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: O
Product: CCNC(=O)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
Ethyl isocyanate (62.0 μl) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (200 mg) in pyridine (2 ml) at 0° C., and the mixture was stirred at 0° C. for 1.5 hr and at room temperature for 22 hr. The reaction mixture was combined with water to give crystals, which were collected by filtration, washed with diethyl ether and recrystallized from ethyl acetate-methanol-hexane to give the titled compound (161 mg) as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]([F:32])([F:33])[F:19])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(=O)c1csc(Cn2ncc(NC(=O)/C=C/c3ccccc3C(F)(F)F)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@H:16]4[C:28]#[N:29])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[CH2:17][C@H:16]4[C:28]#[N:29])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@H](C#N)C[C@@H]2O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 558 mg (1.45 mmol) of 45 in THF (6.6 mL) and MeOH (34 mL) was stirred at rt as 400 mg (10.6 mmol) of NaBH4 was added in small portions over 10 min. The reaction was stirred at rt under N2 for 3.5 h, the solvent was evaporated and the residue was dissolved in EtOAc (100 mL) and H2O (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×, 70 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo giving a yellow foam which was used without purification in the next step. Data for 46: TLC, T-2, Rf 0.22; 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 3H, H-18), 3.75 (t, 1H, J=8.7 Hz, H-17α), 5.05 (s, 2H, benzylic-H), 6.75 (d, 1H, J=2.7 Hz, H-4), 6.80 (dd, 1H, J=8.5, 2.7 Hz, H-4), 7.21 (d, 1H, J=8.5 Hz, H-1), 7.33–7.45 (m, 5H, Ar—H).
Reaction SMILES: [CH:1]1([CH:6](Cl)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(C(C)=O)C(C)C>[CH:1]1([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:19][CH2:20]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Reactant: ClC(c1ccccc1)C1CCCC1
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)C2CCCC2)CC1
Reaction time: 72 h
Yield: 20.1 %

Procedure:
Into 35 ml of methyl isobutyl ketone were dissolved 2.92 g of cyclopentyl-phenylmethyl chloride, 2.80 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 1.94 g of N,N-diisopropylethylamine, and the resultant solution was heated under reflux with stirring for 72 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethyl acetate-ethanol-dichloromethane (1:1:1) by silica gel column chromatography to give 0.88 g of oily 4-(cyclopentyl-phenylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH3:31][N:32]=[C:33]=[S:34]>>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23]([NH:24][C:33]([NH:32][CH3:31])=[S:34])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CN=C=S
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=S)NC)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)methyl)-6-(methylaminothiocarbonyl aminosulfonyl)-7-ethoxychroman ##STR53## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman is synthesized analogously to Example 14 from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-ethoxychroman and methyl isothiocyanate. Melting point: 178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([NH2:26])=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C(N)=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C#N)c12
Yield: 67.1 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (850 mg 2.07 mmol) in N,N-dimethylformamide (10 mL) was added thionyl chloride (0.448 mL, 6.21 mmol). The resultant mixture was stirred at 50° C. for 30 min and poured into saturated aqueous sodium hydrogen carbonate at 0° C. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether to give the title compound as a colorless solid (532 mg, 1.39 mmol, 67%).
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)([O-:6])=[O:5].[CH2:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:17][CH3:18]>C(#N)C>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:19]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCCNc1ccc(Cl)cc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCO
Product: CCCN(C(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1

Procedure:
1.09 g of 2-chlorobenzoylisocyanate was added to a solution of 2.00 g of N-(4-aminophenyl)-N'-(4-chlorophenyl)-N'-propylurea in 50 ml of acetonitrile while stirring at room temperature. After stirring for 1.5 hours at room temperature the formed precipate was sucked off, washed with diethyl ether, and dried. According to PMR the product had the desired structure; the product melted at 170° C. The starting aniline was obtained from the corresponding nitro compound by reduction with hydrogen under the influence of Raney nickel as a catalyst; in this reaction ethanol was used as a solvent. N-(4-nitrophenyl)-N'-(4-chlorophenyl)-N'-propylurea was prepared by a coupling of p-nitrophenylisocyanate with N-propyl-4-chloroaniline in acetonitrile as a solvent. In a corresponding manner, in which, if desired, instead of acetonitrile diethyl ether was used as a solvent for the first-mentioned reaction, the following compounds were prepared; the compound numbers correspond again with the number given before in the specification:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16]C)=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[C:21]([C:38]([F:41])([F:40])[F:39])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(O)(C)(C)C>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=4)[N:5]=[CH:4][C:3]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:20][C:21]=2[C:38]([F:40])([F:41])[F:39])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.1 %

Procedure:
Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.84 mmol) and tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (0.766 g, 2.22 mmol) were dissolved in a mixture of dichloromethane (5 mL) and tert-butanol (5 mL), to the system added potassium carbonate (0.612 g, 4.43 mmol). The reaction mixture was stirred at room temperature for 24 h, suction filtrated, the solid was washed with 30 mL of dichloromethane, and the resulting wash solution and the filtrate were combined, concentrated under reduced pressure, and the resulting residue was recrystallized from diethyl ether to give 0.73 g of a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([NH:21][CH3:22])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH2:23]([N:28]=[C:29]=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:22])[C:29]([NH:28][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:30])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCCCCN=C=O
Reactant: CCO[C@@H](Cc1ccc(-c2cnc(NC)s2)cc1)C(=O)OC
Product: CCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)s1
Yield: 26.1 %

Procedure:
In a manner similar to that of Example 7i, starting with 0.17 g (0.53 mmol) of methyl 2(S)-ethoxy-3-[4-(2-methylaminothiazol-5-yl)phenyl]propionate and 0.14 ml (1.1 mmol) of pentyl isocyanate, 0.06 g (26%) of methyl 2(S)-ethoxy-3-{4-[2-(1-methyl-3-pentylureido)thiazol-5-yl]phenyl}propanoate is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[O:32])([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:8]([F:10])[CH:9]=1)(=[O:3])[CH3:2].[CH3:39][Li]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[O:32])([C:6]2[CH:5]=[C:4]([C:1]([OH:3])([CH3:39])[CH3:2])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: [Li]C
Reactant: CC(=O)c1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of (R)-1-(1-(3-acetyl-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 257, 20 mg, 0.037 mmol) in THF (1 mL) at 0° C. under argon was added dropwise CH3Li (1.4 M in Et2O, 0.04 mL, 0.056 mmol.). The reaction mixture was stirred at room temperature for 2 h, then quenched with sat. NH4Cl and 0.5 N HCl and the aqueous layer was extracted with EtOAc. The combined organic portions were washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 258, 8 mg, yield 39%). LCMS: RT=3.89 min [M+H] 559.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4Cl; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 7.51-7.45 (m, 2H), 7.21-6.96 (m, 6H), 6.68 (d, J=6.8 Hz, 2H), 6.61 (d, J=9.9 Hz, 1H), 5.43 (s, br, 1H), 5.17 (m, 1H), 4.01 (d, J=13.2 Hz, 1H), 3.85-3.62 (m, 3H), 1.46 (s, 3H), 1.44 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:26]=[C:25]([S:27]([CH2:30][CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:34]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:23]2[CH:24]=[C:25]([S:27]([CH2:30][CH:31]([CH3:32])[CH3:33])(=[O:28])=[O:29])[CH:26]=[CH:21][C:22]=2[CH3:34])[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)CC(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)CC(C)C)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-bromo-4-(isobutylsulfonyl)-1-methylbenzene (Intermediate 66), the title compound was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:23])([CH:21]=[CH2:22])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20])[OH:4]>C(OCC)(=O)C.[Pd]>[F:23][C:2]([F:1])([CH2:21][CH3:22])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH3:20])[OH:4]
Reactant: C=CC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C
Yield: 96.7 %

Procedure:
740 mg 2,2-Difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol were dissolved in 50 ml ethyl acetate. 50 mg palladium (5% on charcoal) were added and the reaction mixture stirred at room temperature under a hydrogen atmosphere. After three hours the catalyst was filtered off and the filtrate evaporated in vacuo to obtain 720 mg 2,2-Difluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butan-1-ol as a white solid.