Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:26]([O:25][C:24](=[O:33])[NH:23][C@H:17]([C@H:18]([OH:22])[C:19]([CH3:21])=[CH2:20])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=C(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=C(C)[C@@H](O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Ketone 12 (2.81 g, 4.30 mmol) was dissolved in MeOH (25 mL) and cooled to 0° C. To this were added CeCl3.7H2O (1.5 eq., 6.45 mmol, 2.43 g) and NaBH4 (1.4 eq., 6.0 mmol, 227 mg) portion-wise and the mixture was stirred for 5 minutes. after which TLC analysis indicated a complete conversion. Glacial acetic acid (10 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and extracted with half saturated aq. NaHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo. The title compound was obtained as a colourless oil (yield: 1.79 g, 3.94 mmol, 92%). 1H NMR (400 MHz, CDCl3): δ=7.31-7.01 (m, 9H), 5.30 (d, J=9.18 Hz, 1H), 5.06 (s, 1H), 5.00 (d, J=5.19 Hz, 1H), 4.96-4.91 (m, 3H), 4.21 (d, J=4.41 Hz, 1H), 4.16-4.11 (m, 1H), 4.07-3.98 (m, 1H), 2.85 (d, J=12.55 Hz, 1H), 2.65 (dd, J=13.60, 10.41 Hz, 1H), 1.77 (s, 3H), 1.44 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=155.96, 155.85, 144.44, 137.34, 136.44, 129.34, 128.19, 127.77, 127.66, 127.25, 112.17, 79.25, 76.65, 66.27, 54.06, 44.15, 33.69, 28.22, 18.73 ppm. [α]D23=−18.7 (c=1, CHCl3). HRMS: calcd. for C26H34N2O5 455.25405 [M+H]+. Found 455.25392.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])[C:5]2=O.Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])/[C:5]/2=[N:23]/[NH:24][C:25]([NH2:27])=[O:26]
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(N)ccc21)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2cc(N)ccc21)C(C)C
Yield: 74 %

Procedure:
By using 5-amino-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-5-amino-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 221°-222° C. (decomposition) (yield: 74.0%, recrystallizing solvent: chloroform-methanol).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=CCc2nccn2Cc2ccccc2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C=CCc2nccn2Cc2ccccc2)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (3 g; 7 mmol), sodium hydroxide (0.8 g; 20 mmol) and distilled water (5 ml) in methanol (50 ml) was refluxed for 4 hours. After evaporation to dryness and acidification to pH 6 with 6N HCl, the resulting solid was triturated with water and ether to give 4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid as a mixture of E and Z isomers.
Reaction SMILES: ClCC([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13][C@@H:12]1[OH:34])=O.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+].O>CO>[OH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13][C@@H:12]1[OH:34]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCO)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 50 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
2β-(4'-Chloroacetoxy-n-butoxy)-3α-hydroxy-5α-pregnane-11,20-dione (380 mg.) was dissolved in methanol (40 ml.) and the stirred solution heated to 50°C. Perchloric acid (0.5 ml.) was added and the mixture stirred at 50°C for 5 hours. The mixture was neutralised with sodium bicarbonate solution, poured into water and extracted with ether (2 × 100 ml.). The combined extracts were washed with water (200 ml.), dried over anhydrous sodium sulphate and evaporated in vacuo to a white foam (270 mg.) which was purified by preparative tlc in acetone/petroleum ether 1/1 to give the title compound (170 mg.) [α]D + 79.5°
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][O:13][CH:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])=[CH:22][CH:21]=4)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])[CH2:15]3)[C:6]=2[N:5](COCC[Si](C)(C)C)[C:4]1=[O:58])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][O:13][CH:14]3[CH:19]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])=[CH:24][CH:25]=4)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])[CH2:15]3)[C:6]=2[NH:5][C:4]1=[O:58])[CH3:2]
Reactant: CCn1c(=O)n(COCC[Si](C)(C)C)c2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)[nH]c2c(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cccc21
Temperature: 25 °C

Procedure:
A solution of 0.310 g of benzyl 3-[1-ethyl-2-oxo-3-(2-trimethylsilanylethoxymethyl)-2,3-dihydro-1H-benzimidazol-4-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 4 ml of tetrahydofuran is admixed with 6 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran). The reaction solution is heated to reflux over 48 hours, subsequently cooled to room temperature and admixed with 40 ml of water. The mixture is extracted with tert-butyl methyl ether (2×40 ml) and the combined organic phases are washed with 40 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.18 (3:1 EtOAc-heptane); Rt=5.66.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>>[C:13]([S:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:17])[N:2]([NH:1][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[N:11]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)Sc1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CC(C)(C)Sc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 198B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.32 (d, J=7.9, 1H), 8.12 (d, J=8.0, 1H), 8.01 (t, J=7.6, 1H), 7.93 (t, J=7.5, 1H), 7.44-7.37 (m, 4H), 3.70 (s, 2H), 1.43 (s, 9H); MS (DCI+) M/Z 419 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][CH:4]=1.C1COCC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1>C(=O)=O.CC(C)=O>[OH:13][C@@:12]([CH3:15])([CH2:14][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COc1ccc(NC(=O)[C@]2(C)CO2)cc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(C[C@](C)(O)C(=O)Nc2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a 500 mL single-necked round-bottomed flask fitted with a stirring bar, rubber stopper and a nitrogen inlet was added (S)—N-(4-methoxyphenyl)-2-methyloxirane-2-carboxamide (1.00 g, 4.83 mmol) and anhydrous THF (50 mL). The solution was cooled to −78° C. in dry ice-acetone bath. 4-Methoxyphenylmagnesium bromide solution (14.50 mL of 0.5 M THF solution, 7.25 mmol) was added dropwise with stirring at −78° C. The resulted solution was stirred at −78° C. for 30 minutes and then at room temperature for 3 hours. The reaction was quenched by adding 20 mL of saturated NH4Cl solution at 0° C. EtOAc (3×30 mL) was added to extract the solution. The organic layers were separated, washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, (S)-2-hydroxy-N,3-bis(4-methoxyphenyl)-2-methylpropanamide (6c), 0.60 g, 39.5% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])(=O)=O)=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
(4-Chloro-2-nitro-phenyl)-(3-methanesulfonyl-propyl)-carbamic acid tert-butyl ester was prepared according to Scheme 1. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt %). The mixture was stirred for 30 min at RT, then 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (0.75 g, 2.56 mmol) was added. The solution was heated to 50° C. and stirred for overnight. After cooled to RT, H2O (30 mL) was added and the solution was extracted with DCM (40 mL×3). The organic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC (DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESI+) [(M+H)+]: 393.0.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[CH3:27][C:25]1[CH:24]=[CH:23][C:15]2[S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[CH2:13][C:14]=2[CH:26]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
5.4 g of 1-carbethoxy-4-(10,11-dihydro-2-methyl-dibenzo-[b,f]thiepin-10-yl)-piperazine, 80 ml of ethylene glycol, 4.64 g of potassium hydroxide and 0.33 ml of water and heated for 0.75 hour at 160° C. Then the mixture is poured on to water, extracted with ether, the extracts washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. There is obtained 1-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]=[C:12]([OH:14])[CH:13]=2)=[C:6]([NH:27][C@H:28]([C:30]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34](=[O:42])[C:33]3=[C:43]([CH3:46])[CH:44]=[CH:45][N:32]3[N:31]=2)[CH3:29])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]=[C:12]([OH:14])[CH:13]=2)=[C:6]([NH:27][C@H:28]([C:30]2[N:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:34](=[O:42])[C:33]3=[C:43]([CH3:46])[CH:44]=[CH:45][N:32]3[N:31]=2)[CH3:29])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(O)cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(NS(=O)(=O)c4ccc(O)cc4)c3)n(-c3ccccc3)c(=O)c12
Yield: 38 %

Procedure:
(S)—N-(3-(4-amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-hydroxyphenyl)-4-methoxybenzenesulfonamide (25 mg, 0.04 mmol) was treated with boron tribromide (1M in dichloromethane, 118 μl, 0.12 mmol) in dichloromethane (3 ml) according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 10 mg (38% yield) as a solid. Purity 93%.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)[CH2:16][CH2:15]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[CH2:15][CH2:16][CH:17]([CH:20]([OH:28])[C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)[CH2:18][CH2:19]3)=[CH:11][N:10]=[CH:9]2)=[CH:29][CH:30]=1)#[N:2]
Reactant: Cc1cccc(C(=O)C2CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C(O)C2CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-(3-methylbenzoyl)piperidine (175 mg, 0.44 mmol; Example 104) in methanol (5 mL) was treated with sodium borohydride (12 mg, 0.31 mmol) at room temp. The resultant solution was stirred at room temp. for 30 min., and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[NH:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][C:14]=1[CH3:21])=O>>[CH3:21][C:14]1[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[NH:17][C:13]=1[CH:11]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2ccccc21
Yield: 100 %

Procedure:
Oxindole (133 mg, 1 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (153 mg) using method D to give 268 mg (100%) of the title compound as an orange-red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:21]([Cl:26])=[O:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: CSc1ccc(-c2cc(C(=O)Cl)nn2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (13.5 g) and thionyl chloride (10 ml) in dichloroethane (30 ml) was refluxed for 1 hour. The mixture was concentrated to give an oil of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carbonyl chloride.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)C.O>C1(C)C=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=2[CH:4]=[CH:5]1
Reactant: CCOC(COc1ccc(C(C)=O)cc1)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2occc2c1
Yield: 3.7 %

Procedure:
To a solution of 1-(4-(2,2-diethoxyethoxy)phenyl)ethanone (2.46 g, 7.34 mmol) in toluene (25 mL), was added PPA (2.50 g) and refluxed for 1 hour. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (44 mg (yield 3.7%)) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@@H:18]([CH:20]4[CH2:22][CH2:21]4)[CH3:19])=[C:15]([C:23]([NH2:25])=[O:24])[CH:14]=[N:13][N:12]3[CH:26]=2)[CH:6]=[CH:7][CH:8]=1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:20]1([C@H:18]([NH:17][C:16]2[C:11]3[N:12]([CH:26]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:4]=4)[CH:10]=3)[N:13]=[CH:14][C:15]=2[C:23]([NH2:25])=[O:24])[CH3:19])[CH2:22][CH2:21]1
Reactant: CC(C)C(=O)O
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CN)c3)cc12)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCc1cccc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-4-(((1R)-1-cyclopropylethyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 87, 15 mg, 0.043 mmol), isobutyric acid (3.99 μl, 0.043 mmol) and triethylamine (8.97 μl, 0.064 mmol) in DMF (0.5 mL) was added BOP (18.99 mg, 0.043 mmol) followed by stirring at rt for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (8.7 mg, 48%). HPLC (condition H): retention time=1.69 minute. LC/MS (M+H)+=420.3. 1H NMR (500 MHz, MeOD) δ ppm 8.04 (1 H, s), 7.82 (1 H, d, J=1.9 Hz), 7.48-7.52 (2 H, m), 7.33 (1 H, t, J=7.9 Hz), 7.15 (1 H, d, J=7.5 Hz), 7.06 (1 H, d, J=1.7 Hz), 4.41 (2 H, s), 4.04 (1 H, qd, J=6.4, 6.2 Hz), 2.48 (1 H, spt, J=6.9 Hz), 1.44 (3 H, d, J=6.4 Hz), 1.16 (6 H, d, J=6.9 Hz), 1.09-1.15 (1 H, m), 0.50-0.63 (2 H, m), 0.32-0.40 (2 H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([SH:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([S:23][CH:21]([CH3:22])[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 32 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (300 mg), isopropylthiol (0.121 mL) and potassium carbonate (451 mg) in DMF (5 mL) was stirred with heating at 100° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 3→40% ethyl acetate/hexane), and further by preparative HPLC to give the title compound (111 mg, 32%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]3[C:10]=2[C:5](=[CH:6][CH:7]=[CH:8]3)[CH:4]([C:15]#[N:16])[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:28](N)[CH2:29][NH2:30]>>[CH3:1][CH:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]3[C:10]=2[C:5](=[CH:6][CH:7]=[CH:8]3)[CH:4]([C:15]2[NH:30][CH2:29][CH2:28][N:16]=2)[O:3]1
Reactant: NCCN
Reactant: CC1OC(C#N)c2cccc3cccc1c23
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1OC(C2=NCCN2)c2cccc3cccc1c23
Temperature: 200 °C
Yield: 9.1 %

Procedure:
3-Methyl-1,3-dihydrobenzo[de]isochromene-1-carbonitrile (100 mg) was mixed with ethylene diamine mono-p-toluenesulfonic acid salt (111 mg) and the mixture was heated to 200° C. After 3 hours reaction was cooled to room temperature. Purification of the mixture by column chromatography with neutral alumina (ethyl acetate-heptane) afforded 11 mg of 2-(3-methyl-1,3-dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1H-imidazole that was converted to the title compound using salt formation method A. (Yield 10 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:11])[C:6](=O)[CH3:7].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[N:9]=[C:10]([C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[O:11][C:6]=1[CH3:7]
Reactant: COC(=O)CC(NC(=O)c1ccc(Cl)nc1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
3-[(6-Chloro-pyridine-3-carbonyl)-amino]-4-oxo-pentanoic acid methyl ester is dissolved in acetic anhydride (75 mL) and concentrated sulfuric acid is added in 500 uL portions five times over a four hour period. The reaction is monitored by HPLC. The reaction is then heated to 40° C. until the starting material is consumed. The reaction is allowed to proceed at room temperature overnight. The reaction is then concentrated to dryness and purified by column chromatography. This procedure yielded (12.8 g, 48 mmol) 22% of the desired oxazole over four steps.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([Cl:20])[CH:11]=1)[CH2:5][CH:6]1[CH2:9][O:8][CH2:7]1.O.[OH-].[Li+]>CO.O>[Cl:20][C:12]1[CH:11]=[C:10]([CH:4]([CH2:5][CH:6]2[CH2:9][O:8][CH2:7]2)[C:3]([OH:21])=[O:2])[CH:15]=[CH:14][C:13]=1[S:16]([CH3:19])(=[O:17])=[O:18]
Reactant: COC(=O)C(CC1COC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2COC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-oxetan-3-yl-propionic acid methyl ester (1.0 g, 3.00 mmol) was dissolved in methanol (50 ml) and treated with a solution of lithium hydroxide monohydrate (0.50 g, 11.92 mmol) in water (1 ml) at 25° C. It was stirred at 25° C. for 1.5 h. The reaction was then concentrated in vacuo to remove the methanol. The remaining aqueous layer was then diluted with water and acidified to pH=3 with an aqueous 1N hydrochloric acid solution. This was then extracted with methylene chloride (3×50 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-oxetan-3-yl-propionic acid (0.87 g, 91%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.01-2.14 (m, 1H, CH of CH2), 2.25-2.41 (m, 1H, CH of CH2), 2.75-2.89 (m, 1H, CH), 3.36 (s, 3H, SO2CH3), 3.68 (t, J=7.8 Hz, 1H, ArCHCO), 4.13 (t, J=6.3 Hz, 1H, OCH of OCH2), 4.27 (t, J=6.3 Hz, 1H, OCH of OCH2), 4.44 (dd, J=7.9, 5.9 Hz, 1H, OCH of OCH2), 4.57 (dd, J=7.9, 5.9 Hz, 1H, OCH of OCH2), 7.54 (dd, Jo=8.1 Hz, Jm=1.7 Hz, 1H, Ar), 7.68 (d, Jm=1.7 Hz, 1H, Ar), 8.00 (d, Jo=8.1 Hz, 1H, Ar), 12.77 (brs, 1H, CO2H).