Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Nc3cccc(Cl)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-chloro-phenylamine to give N1-(3-chloro-phenyl)-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 350(MH+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:3]=1[CH:4]=[O:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)(=O)C>[N:15]1([C:2]2[CH:9]=[CH:8][C:7]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1cc(-c2cccs2)ccc1F
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2cccs2)ccc1N1CCCC1
Yield: 32 %

Procedure:
Ex-63A: A solution of 2-fluoro-5-thiophen-2-yl-benzaldehyde (1.42 g, 6.89 mmol) in pyrrolidine was refluxed (10 mL). After 4.5 days the reaction mixture was cooled and diluted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0.5M) sodium carbonate (2M) and saturated solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (20%, v/v, in hexane) afforded 2-pyrrolidin-1-yl-5-thiophen-2-yl-benzaldehyde (0.5 g, 32%). 1H NMR (CDCl3) δ 10.14 (s, 1H), 7.94 (d, J=2 Hz, 1H), 7.62 (dd, J=2.7, 9 Hz, 1H), 7.22–7.20 (m, 2H), 7.07–7.04 (m, 1H), 6.86 (d, J=9 Hz, 1H), 3.41 (m, 4H), 2.01 (m, 4H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: COCCOCCl
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1ccc(Cl)cc1C(=O)O
Reaction time: 18 h
Yield: 81.8 %

Procedure:
Sodium hydroxide (7.20 g, 180 mmol) was added to a solution of 5-chlorosalicylic acid (10.36 g, 60 mmol) in tetrahydrofuran (60 ml). (2-Methoxyethoxy)methyl chloride (15.1 ml, 132 mmol) was added to the mixture, and the mixture was stirred for 18 hours. 2N Aqueous sodium hydroxide (80 ml) was added to the reaction mixture, and the mixture was refluxed for 2 hours. The water layer was adjusted to pH=3 by addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane ethyl acetate=1:1) to give the title compound (12.8 g, 82%) as a colorless liquid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[CH2:23]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:5]([CH:6]([OH:14])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:4]([OH:30])=[O:3])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C(O)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 5.43 g (13.5 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid ethyl ester in 75 ml tetrahydrofurane were added 2.28 g (53.8 mmol) lithium hydroxide monohydrate dissolved in 13.5 ml water. The mixture was stirred at 60° C. overnight. Water was added followed by extraction with ethyl acetate. The waterphase was adjusted to pH 1 with 1 N aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol 9/1 yielded 3.50 g (69%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-4-phenyl-butyric acid, MS m/e (%): 376.5 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])[NH2:3].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([NH:3][N:2]([CH3:1])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])=[O:23])([OH:18])=[O:17]
Reactant: CN(N)C(=S)Nc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccccc1C(=O)O)C(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-4-phenyl-3-thiosemicarbazide (0.2 mole) was dissolved in 75 ml of dimethylformamide and placed in a 3-necked round-bottomed flask equipped with magnetic stirrer, condenser, additional powder funnel and thermometer. Phthalic anhydride (0.2 mole) was added in portions at 20°. The contents were stirred overnight at room temperature, then poured into ice water. The resulting solid product was recrystallized from a mixture of hexane and ethanol.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:21]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:14]=2)[CH2:9]1)(C)(C)C>C(O)=O>[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:21]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=4)=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:14]=2)[CH2:9]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NC(=O)OC(C)(C)C)C3)c1-c1ccc(C(F)(F)F)cc1
Solvent: O=CO
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of {5-[(6-methyl-4′-trifluoromethylbiphenyl-2-carbonyl)-amino]-indan-2-yl}-carbamic acid tert-butyl ester (5.19 g,10.5 mmol) in formic acid (40 mL) is heated to 40° C. with stirring. After 3 h, the reaction mixture is cooled to room temperature and stirring is continued for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting oil dissolved in ethyl acetate. The organic layer is washed with 8% NaHCO3 solution until the aqueous layer remains basic at which point a precipitate forms in the organic layer. The precipitate is collected by filtration to give 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:22]4[CH:21]=[N:20][C:29]5[C:24]([CH:23]=4)=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cnc5ccccc5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoline-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoline.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=NN.[CH2:18]([N:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:18]([N:24]1[C:25](=[O:30])[CH:26]2[CH:27]([C:4]2([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:3][C:2]([F:17])([F:16])[F:1])[C:28]1=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NN=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN1C(=O)C=CC1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 223.4 %

Procedure:
3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone hydrazone (Preparation 104, 150 mg, 0.6 mmol) was dissolved in dioxan (10 ml) and manganese dioxide (600 mg, 7.1 mmol) was added in one portion at room temperature. After stirring for 30 min, the reaction mixture was filtered through a pad of Arbocel™ directly into a flask containing a stirred solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 44 mg, 0.2 mmol) in dioxan (10 ml). The filter pad was washed further with dioxan (40 ml), and was also added to the reaction mixture. The resulting amber-yellow solution was stirred for 16 h at room temperature. The colourless mixture was then heated under reflux for 1 h before cooling to room temperature and concentrating in vacuo. The residue was purified by chromatography on silica gel (10 g), eluting with hexane:ether (2:1) to give the product as a white solid (178 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Reactant: OCc1ccccc1
Product: O=C(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1O
Yield: 87.3 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-phenylethanone (7.08 g, 31.0 mmol) and benzyl alcohol (3.37 mL, 32.55 mmol), 8.62 g (87%) of the title compound was obtained as a white solid: mp 106-108° C. (lit. 104-105° C.); IR (KBr) 1620, 1572, 1500; 1389, 1352, 1270, 1230, 1192, 1134, 1000, 974, 830, 760, 729, 697, 628, 561 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.69 (br s, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.25-7.39 (m, 10H), 6.49-6.51 (m, 2H), 5.07 (s, 2H), 4.20 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 202.41, 166.20, 16.5.68, 136.22, 134.79, 132.53, 129.76, 129.17, 129.14, 128.76, 127.95, 127.51, 113.77, 108.75, 102.47, 70.66, 45.28; HRMS calculated for C21H18NaO3 (M+Na)+ 341.1154; found 341.1136.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[O:42][CH3:43]>[Cu]I>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:9])=[O:10])=[CH:4][C:3]=2[OH:26])=[C:35]([O:42][CH3:43])[CH:36]=1)#[N:39]
Reactant: COc1cc(C#N)ccc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3ccc(C#N)cc3OC)c(O)c2)cc1
Temperature: 110 °C

Procedure:
A microwave vial was charged with 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.185 g, 0.472 mmol) (INTERMEDIate AD), cesium carbonate (0.384 g, 1.179 mmol), 4-bromo-3-methoxybenzonitrile (0.05 g, 0.236 mmol, Combi Blocks) and copper(i) iodide (0.011 g, 0.059 mmol). The vial was sealed and flushed with argon, and wrapped with aluminum foil to exclude light, then DMF (0.5 mL) was added. The reaction was heated to 110° C. for 2 hr to give intermediate 4-((4-cyano-2-methoxyphenyl)amino)-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide. The reaction was cooled to rt, and chloroacetic acid chloride was added dropwise (0.038 ml, 0.472 mmol). The solution was maintained at rt for 30 min. At this time, 10 mL of saturated ammonium chloride solution was added, and the mixture was further diluted with 10 mL of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). To the aqueous layer was added n-(2-hydroxyethyl)ethylenediaminetriacetic acid, trisodium salt hydrate (500 mg, Sigma Aldrich) to aqueous to decomplex Cu from the product. The resulting aqueous solution was extracted with DCM (1×10 mL). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product, 4-(4-cyano-2-methoxyphenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.133 g, 0.236 mmol, 100% yield) was taken forward without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:30])[C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:38]([O:40][CH2:41][CH3:42])=[CH2:39])CCC>CN(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>[CH2:41]([O:40][C:38]([C:2]1[CH:3]=[C:4]([F:30])[C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1)=[CH2:39])[CH3:42]
Reactant: CN(C)[C@H]1CCN(c2cnc3ccc(Sc4nnc5c(F)cc(Br)cn45)cc3c2)C1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(F)c2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 6.98 %

Procedure:
The solution of (85.1) (175 mg, 0.359 mmol) and PdCl2(PPh3)2 (37.8 mg, 0.054 mmol) in DMF (10 ml) was bubbled by N2 for 5 min. tributyl(1-ethoxyvinyl)stannane (195 mg, 0.539 mmol) was added. The reaction tube was flushed by N2 for 5 min again and sealed. The sealed-tube was stirred at 90° C. for 2 h. Then the reaction was continued at 110° C. for 16 h. The mixture was evaporated to dryness and the residue was purified by column chromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 10%) to afford the target product (40 mg, 30% pure, yield 6.98%). LCMS (method A): [M+H]+=479.1, tR=1.92 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([C:35](O)=[O:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:35]([CH:33]3[CH2:34][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32]3)=[O:36])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 20 mg, 0.06 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (15 mg, 0.072 mmol), and HATU (28 mg, 0.072 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.032 mL, 0.18 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 70% acetonitrile/water to yield the final product as an off-white solid (19 mg, 61% yield). MS (apci) m/z=515.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[N:14]([CH2:17][CH3:18])=[C:15]=[O:16]>CN(C=O)C>[CH2:17]([NH:14][C:15](=[O:16])[NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:18]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)NNC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a mixture of 2-nitro-benzoic acid hydrazide (3 g) in DMF (20 mL) was added isocyanato-ethane (1.3 g). The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo to provide 4 g of 4-ethyl-1-(2-nitrobenzoyl)-semicarbazide: 1H NMR (300 MHz, CDCl3) δ 8.2 (dd, 1H), 7.8 (s, 3H), 6.4 (bs, 1H), 3.3 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:22][CH2:23][CH3:24])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([S:22]([CH2:23][CH3:24])=[O:33])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a mixture of 2-(3-chloro-2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.72 g) and chloroform (10 ml), 3-chloroperbenzoic acid (purity: 69-75%, 0.66 g) was added under ice-cooling, and then heated to room temperature, and stirred for 20 minutes. Into the reaction mixture, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform 2 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.67 g of 2-(3-chloro-2-ethylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 89).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(C(F)(F)F)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:22]([O:24][C:25](=[O:39])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]2[CH:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=2)[N:29]=[N:28]1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:39])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]2[CH:33]=[N:34][C:35]([NH:1][C:2]3[S:3][C:4]([C:10]4[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=4[F:16])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])=[CH:36][CH:37]=2)[N:29]=[N:28]1)[CH3:23]
Reactant: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CCOC(=O)Cn1cc(-c2ccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)nc2)nn1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and ethyl[4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl]acetate (128 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>>[CH2:3]([CH:2]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][OH:5])[CH3:4]
Reactant: CCCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(CC)CO
Temperature: 11 °C
Yield: 56.9 %

Procedure:
101.0 g of n-butyraldehyde and 5.0 g of polyethylene glycol (PEG 400) were placed in a reactor. The mixture was cooled to 11° C., and a total of 171.0 g of a 0.25% aqueous solution of NaOH was added to it at such a rate that the temperature of the mixture remained at 30°-32° C. After 2 hours the mixture was neutralized with hydrochloric acid, the phases were separated, and the organic phase was hydrogenated with Raney nickel at 100° C. and at a hydrogen pressure of 20 bar. The product was analyzed gas chromatographically. The 2-ethyl-1,3-hexane diol yield was 57.7 g, which corresponded to a yield of 56.9%. The worst byproduct, 2-ethyl hexanol, formed in an amount of 1.8%, and the unreacted n-butyraldehyde had become reduced to 1-butanol.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>N1C=CC=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4Cl)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 46.5 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2-chlorobenzenesulfonyl chloride (27 mL, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was purified by chromatography on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (14 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=6.25 Hz, 6 H) 1.54 (m, 2 H) 1.67 (m, 1 H) 4.44 (t, J=7.71 Hz, 2 H) 7.57 (m, 7 H) 8.11 (d, J=8.46 Hz, 1 H) 8.52 (dd, J=8.09, 1.84 Hz, 1 H) 8.86 (dd, J=4.78, 1.84 Hz, 1 H) 11.24 (s, 1 H) 13.99 (s, 1 H). MS (ESI−) m/z 600 (M−H)−.