Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N+:54]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[S:63](Cl)(=[O:65])=[O:64])([O-:56])=[O:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[N+:54]([O-:56])=[O:55])(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccccc1[N+](=O)[O-])O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with 2-nitro-benzenesulfonyl chloride to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-nitro-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (21 mg) was hydrolyzed according to General Procedure B to give the title compound (16 mg). LCMS (m/z): 919.
Reaction SMILES: [Cl:1][C:2]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:28][CH2:29][CH2:30][CH2:31][N:5]([CH2:4][C:3]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:25])([F:26])[F:27])[C:2]=1[Cl:1])[CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCBr
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(CN(CCCBr)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.3 %

Procedure:
A solution of compound (2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amine (2.5 g, 6.5 mmol) and 1,3-dibromo propane (3.2 ml, 32 mmol) in acetonitrile (300 ml) was treated with solid potassium carbonate (1.8 g, 13 mmol). The reaction was heated to reflux and stirred for 48 h. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (EtOAc:Hexane/20:80) to give the title compound as an oil (2.2 g, 67%). MS m/e 510.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([F:35])[CH:37]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2cccc(F)c2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 3-fluoro-benzylbromide (135 μL). The reaction mixture is allowed to stir at room temperature for 18 h. The resulting suspension is poured into water (10 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 425 mg (81%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:24]2[CH:25]=[N:21][NH:22][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cn[nH]c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in dioxane (3 mL) was added 1H-pyrazol-4-ylboronic acid (172.0 mg, 1.54 mmol), K3PO4 (326.0 mg, 1.54 mmol), Pd(PPh3)4 (29.6 mg, 0.03 mmol) and 3 drops water. The resulting solution was stirred for 20 min at 90° C. with an inert atmosphere of nitrogen and then diluted with water (20 mL), extracted with dichloromethane (4×20 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2%-10% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a yellow solid (130 mg, 58.6%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:10][CH2:11][CH:12]([OH:15])[CH2:13]O.O>CC1C=CC(S(O)(=O)=O)=CC=1.CCCCCC>[CH3:5][C:3]1([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[O:15][CH:12]([CH2:11][Cl:10])[CH2:13][O:4]1
Reactant: OCC(O)CCl
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CC1(C)OCC(CCl)O1
Yield: 71.9 %

Procedure:
In a similar manner to the preceding Examples, 65 g (0.5 mol) of ethyl acetoacetate are heated together with 55 g (0.5 mol) of 3-chloro-1,2-propanediol and 0.2 g of p-TSA in a water separator. 100 ml of hexane act as entraining agent. Once 9 ml of water have separated, the reaction mixture is washed with 100 ml of water, to which 1 g of NaOH is added, dried over Na2SO4 and fractionated. 80 g (72%) of 2-methyl-2-ethoxycarbonylmethyl-4-chloromethyl-1,3-dioxolane are obtained. Bp.: 124° C. (1500 Pa); IR: 1736 cm−1 (C═O, ester); MS: m/e=207 (M−15), 181, 173, 157, 144, 135, 115, 99, 75, 57, 43.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[C:7](Cl)(=O)[C:8]([CH3:11])([CH3:10])[CH3:9]>ClCCl.C(N(CC)CC)C>[CH3:9][C:8]([C:7]1[N:2]([CH3:1])[C:3](=[S:6])[NH:4][N:5]=1)([CH3:11])[CH3:10]
Reactant: CNC(=S)NN
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)n[nH]c1=S
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-methyl-3-thiosemicarbazide (0.53 g) in dichloromethane (10 mL) and triethylamine (0.73 mL) was added slowly via syringe pivaloyl chloride (5 mmol). Formation of a precipitate was observed. The mixture was kept overnight. Volatiles were evaporated in vacuo, the residue heated to 80° C. in aqueous NaOH (1 M, 25 mL) for 3 h. Aqueous HCl (2 M) was then added at 25° C. until pH ca. 6. The mixture was concentrated to dryness, water (10 mL) was added and the product collected by filtration, washing with saturated aqueous NaHCO3 (2.5 mL) and then water (10 mL) to give, after drying, the title compound (0.23 g) of ca. 90% purity by NMR as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[F:31][C:32]([F:42])([F:41])[C:33]([NH:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][CH:36]([NH:35][C:33](=[O:34])[C:32]([F:42])([F:41])[F:31])[CH2:37]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: O=C(NC1CCNC1)C(F)(F)F
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(NC(=O)C(F)(F)F)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
N-(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidin-3-yl)-2,2,2-trifluoro-acetamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2,2,2-Trifluoro-N-pyrrolidin-3-yl-acetamide following General Procedure B.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18].O>CN(C=O)C>[F:12][C:2]([F:11])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:16][C:17]([OH:19])=[O:18])[CH:4]=1
Reactant: OCc1cc(C(F)(F)F)ccn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COCc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [4-(trifluoromethyl)pyridin-2-yl]methanol (340 mg, 1.9 mmol) in DMF (10 mL) was added sodium hydride (150 mg, 3.8 mmol). After being stirred at room temperature for 5 min. 1,1-dimethylethyl bromoacetate (0.28 mL, 1.9 mmol) was added. Stirring was continued at room temperature for 1 h. Water (20 mL) was added and the resulting solution was extracted with EtOAc. The water layer was neutralized to pH=5 with HCl and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum to give the title compound which was used for the next reaction without purification. MS (M+H) 292.2.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1Cl
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1Cl

Procedure:
3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 44.3 ml of thionyl chloride were refluxed for 5 hours. After cooling down, the reaction mixture was evaporated under vacuum to yield 3.5 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](I)[CH:16]=[CH2:17].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:17][CH:16]=[CH2:15])=[CH:4][CH:3]=1
Reactant: C=CCI
Reactant: O=c1ccc2ccc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ccc(F)cc21
Yield: 47.7 %

Procedure:
To a suspension of 7-fluoro-2(1H)-quinolinone (1.53 g, 9.39 mmol) in DMF at 0° C. was added sodium hydride (0.83 g of a 60% w:w dispersion in oil, 20.65 mmol) and the reaction was allowed warm to rt over 0.5 h before addition of allyl iodide (1.91 ml, 20.65 mmol). The reaction was stirred at rt for a further 0.25 h before addition of water (100 ml). The aqueous phase was then extracted with 10% MeOH in DCM (3×200 ml) and the combined organic phases were dried, evaporated and the residue was subjected to column chromatography on silica gel using a 10% MeOH in DCM gradient to provide the desired compound (0.91 g, 48%). This material contained approximately 10% of the isomeric 5-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone.
Reaction SMILES: [C:1]1([CH:7]([O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br-:31].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:1]1([CH:7]([O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21][Br:31])=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Br-]
Reactant: OCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: BrCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To an ice cold solution of 6-5 (1.19 g, 6.0 mmol) in acetonitrile (15 ml) was added pyridine (0.76 g, 9.6 mmol) and then triphenylphosphine dibromide (3.29 g, 7.8 mmol). The mixture was stirred at ice bath temperature for 1/4 hr under N2 and at ambient temperature for 1 &3/4 hrs and then was filtered. Concentration of the filtrate in vacuo gave a crude oil. The pure product 6-6 was obtained after three silica gel chromatographic separations.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[N:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>C(#N)C>[Cl:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=2)[N:24]=1
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
To a dry flask containing a magnetic stir bar and a nitrogen atmosphere was added 0.247 g (1.33 mmol) of 3-[(methylsulfonyl)methyl]aniline, 2 mL dry acetonitrile and 0.23 mL (1.3 mmol) of diisopropylethyl amine and resultant mixture cooled in an ice bath. To the cold solution was added a solution of 0.2 g (1.33 mmol) of 2,4-dichloro-1,3,5-triazine in 2.4 mL of dry acetonitrile over 1 min. The reaction mixture was stirred for ca. 16 hrs and 1 gram of silica gel was added. The mixture was concentrated in vacuo to dryness and applied to the top of column of silica gel and eluted with a 15-50% ethyl acetate/dichloromethane gradient. The proper fractions were combined and concentrated in vacuo to give 0.28 g (70%) of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine as a white solid. HNMR: δ 10.83 (s, 1H), 8.64 (s, 1H), 7.63 (m, 2H), 7.4 (t, 1H), 7.25 (d, 1H), 4.48 (s, 2H), 2.94 (s, 3H); MS (ES+, m/z) 299, 301 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][N:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: CC(C)c1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C(C)C)c3)nc12

Procedure:
From 2-isopropyl-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]([CH3:18])([CH2:16][OH:17])[CH2:14][OH:15]>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:12]([C:13]([CH3:18])([CH2:16][OH:17])[CH2:14][OH:15])[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde (Preparation 208) and 2-amino-2-methylpropane-1,3-diol to afford the title compound as a yellow liquid in 79% yield, 3.88 g.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([OH:37])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:56]1[C:61]([F:62])=[C:60]([F:63])[C:59]([F:64])=[C:58]([F:65])[C:57]=1[F:66])=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](=[O:37])[O:36][C:56]3[C:57]([F:66])=[C:58]([F:65])[C:59]([F:64])=[C:60]([F:63])[C:61]=3[F:62])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.25 h

Procedure:
To a second flask containing #32 (360 mg, 0.59 mmol) in dichloromethane (0.6 mL, 1 M) and pyridine (0.095 mL, 1.2 mmol, 2 eq.) was added drop-wise pentafluorophenyl trifluoroacetate (0.203 mL, 1.18 mmol). This reaction mixture was stirred for 15 minutes.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:22]3[N:23]=[C:24]([Cl:28])[N:25]=[C:26]([Cl:27])[C:21]=3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:29][C:30]([CH3:32])=[O:31]>C1COCC1>[C:9]1([S:15]([N:18]2[C:22]3[N:23]=[C:24]([Cl:28])[N:25]=[C:26]([Cl:27])[C:21]=3[CH:20]=[C:19]2[C:30]([OH:31])([CH3:32])[CH3:29])(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)nc(Cl)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Lithium diisopropylamide (2 mL, 4.0 mmol, 2 M in THF) was added dropwise to a solution of 7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (656 mg, 2.0 mmol) in anhydrous THF (15 mL) at −78° C. The resulting solution was stirred at −78° C. for 90 min, then acetone (0.4 mL, 5.5 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo affording 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol. To a solution of 2-(7-benzenesulfonyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (2 mmol) in a mixture of isopropyl alcohol (11 mL) and water (3 mL) was added sodium hydroxide (6 mL, 36 mmol, 6M aqueous solution). The resulting mixture was stirred at RT for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 2-(2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 64%). LCMS (method A): RT=2.70 min, [M]−=244/246.
Reaction SMILES: C(C1C=C(C#N)C(=O)NC=1[CH:10]=[CH:11][N:12]([CH3:14])[CH3:13])(=O)C.[C:18]([C:21]1[CH:22]=[C:23]([C:29]#[N:30])[C:24](=[O:28])[NH:25][C:26]=1C)(=[O:20])[CH3:19].COC(OC)N(C)C>CO>[C:18]([C:21]1[CH:22]=[C:23]([C:29]#[N:30])[C:24](=[O:28])[N:25]([CH:10]=[CH:11][N:12]([CH3:14])[CH3:13])[CH:26]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Agent: COC(OC)N(C)C
Solvent: CO
Product: CC(=O)c1cc(C#N)c(=O)n(C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
D-3. 5-Acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile--A mixture containing 35.2 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 300 ml of methanol and 30 ml of dimethylformamide dimethyl acetal was heated with stirring on a steam bath for 4 and 1/2 hours and then allowed to cool to room temperature. The precipitated yellow solid was collected, washed with methanol and dried in an oven under reduced pressure at 95° C. to yield 16.4 g of 5-acetyl-1,2-dihyro-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile, m.p. 267°-270° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([C:53](=[O:64])[C@H:54]([NH:62][CH3:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH:49][C:50](=[O:52])[CH3:51].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:10]([C:11](=[O:13])[N:62]([C@H:54]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:53]([N:48]([CH3:47])[NH:49][C:50](=[O:52])[CH3:51])=[O:64])[CH3:63])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)NC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 2(R)-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.18 g, 0.53 mmol) in methylene chloride (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.072 g, 0.53 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.53 mmol) and the mixture was cooled to 0° C. Then acetic acid N'-methyl-N'-((2R)-2-(methylamino)-3-phenylpropionyl)hydrazide (0.11 g, 0.44 mmol) and diisopropylethylamine (0.098 ml, 0.57 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered, concentrated in vacuo and chromatographed on silica gel (40 g) with ethyl acetate to give 0.14 g (57%) of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [Br:1]Br.[S:3]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:4]1[S:3][C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=1
Reactant: CN1CCC(=C2c3ccccc3CCc3sccc32)CC1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(=C2c3ccccc3CCc3sc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Bromine (1.0 mL, 19.5 mmol) was added dropwise to a chloroform (50 mL) solution of 4-(9,10-dihydro-1-thiabenzo[f]azulen-4-ylidene)-1-methylpiperidine (5.76 g, 19.5 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. Thereafter, a saturated aqueous sodium bicarbonate solution was added to the mixture, and an organic layer was separated. The organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue was purified by column chromatography (chloroform-methanol=9:1), to give 5.6 g (91%) of the captioned compound in the form of white crystals.