Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one (130c) (240 mg, 0.636 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (336 mg, 0.763 mmol), Pd(PPh3)4 (37 mg, 0.0318 mmol), Na2CO3 aqueous solution (1.0 N, 2.1 mL, 2.1 mmol), 1,2-dimethoxyethane (4.2 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 242a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.[CH3:12][S-:13].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:13][CH3:12])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Br)nc(Br)c1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 2,6-dibromo-4-nitro-pyridine (CAS 175422-04-5, 10.0 g, 35.5 mmol) in 60 mL of DMF was added at −10° C. sodium methanethiolate (2.61 g, 1.05 eq.) and the mixture stirred for 45 Min. at this temperature and for another 2 h at 0° C. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=97/3), yielded 8.55 g of the title compound as off-white crystals.
Reaction SMILES: C[C:2]1[C:6]([CH2:7]Cl)=[C:5]([CH2:9]Cl)[S:4][C:3]=1[C:11]([OH:13])=[O:12].[CH3:14]N.[C:16](#[N:18])C>>[CH3:16][N:18]1[CH2:7][C:6]2[CH:2]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[S:4][C:5]=2[CH2:9]1
Reactant: CC#N
Reactant: CN
Reactant: Cc1c(C(=O)O)sc(CCl)c1CCl
Product: COC(=O)c1cc2c(s1)CN(C)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4,5-bis(chloromethyl)-2-thiophenecarboxylic acid (D. J. Zwanenburg and Hans Wynberg, J. Org. Chem., 34, 333-340, (1969)) (520 mg) was dissolved in acetonitrile (600 ml), methylamine (40% methanol solution, 722 μl) was added to the solution, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride:methanol=1:0→19:1) to obtain the title compound (176 mg).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[O:18][CH3:19].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>CO>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[O:18][CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: COc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Solvent: CO
Product: COc1cc(C2=NNC(=O)CC2)ccc1OCC(O)CNC(C)(C)C
Yield: 95.8 %

Procedure:
A stirred mixture of 6-[4-(2,3-epoxypropoxy)-3-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (1.2 g, 0.0043 mole), methanol (24 ml), and t-butylamine (2.76 ml, 0.026 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave a glassy residue (1.44 g, 95%). The crude hemisulphate of 6-[4-(3-t-butylamino-2-hydroxypropoxy)-3-methoxyphenyl]-4,5-dihydro-3(2H)-pyridazinone (m.p. 266°-268.5°C) was recrystallised from methanol-ether to give the pure hemisulphate m.p. 270°-272°C decomposition.
Reaction SMILES: C([Li])(C)(C)C.[O:6]1[C@H:8]2[C@:9]3([CH2:25][CH2:24][C@H:23]4[C@@H:14]([CH2:15][CH2:16][C:17]5[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[CH:21][C:22]=54)[C@@H:12]3[CH2:13][C@@H:7]12)[CH2:10][CH3:11].O>CCCCC.CCOCC>[CH3:27][O:26][C:19]1[CH:20]=[CH:21][C:22]2[C@@H:23]3[C@H:14]([C@H:12]4[C@@:9]([CH2:25][CH2:24]3)([CH2:10][CH3:11])[C@H:8]([OH:6])[CH:7]=[CH:13]4)[CH2:15][CH2:16][C:17]=2[CH:18]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C[C@H]1O[C@H]12
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Solvent: CCCCC
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C=C[C@H]2O
Reaction time: 1 h

Procedure:
At 0° C. and under argon, 4 ml. of a 2-molar tert.-butyllithium solution in pentane is added to 450 mg. of 16α,17α-epoxy-3-methoxy-18-methyl-1,3,5(10)-estratriene in 12 ml. of ether. After 1 hour, the solution is diluted with ether, gently mixed with water, washed neutral, and dried over sodium sulfate. After purifying the crude product by preparative layer chromatography (system: hexane/ethyl acetate = 7 : 3), 140 mg. of 3-methoxy-18-methyl-1,3,5(10),15-estratetraen-17α-ol is obtained as an oily product. [α]D 20 = -105°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CC(=O)c1ccc(-n2ccnc2)nc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a 25 mL vial which contained 1-(6-chloro-pyridin-3-yl)-ethanone (1.5 g, 10 mmoL) was added 1H-imidazole (3 g, 50 mmoL) at rt. The mixture was stirred at 120-130° C. for 2 h and cooled to rt. The contents were poured into 150 mL ice-water solution and extracted with EtOAc (3×100 mL). The combined organic layers was washed with water (3×50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under vacuum to yield the crude which was purified by column to afford desired 1-(6-imidazol-1-yl-pyridin-3-yl)-ethanone (1.25 g, 67%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:44])[F:43])=[N:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:43])[F:44])=[N:20][N:21]([C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Reactant: Cn1[nH]c(=O)c2c1[C@@]1(C)CC[C@@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 58.7 %

Procedure:
A solution of (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 48; 250 mg, 1.2 mmol) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole (Intermediate 2; 580 mg, 1.2 mmol) in dimethylformamide (12 mL) was heated at 100° C. for 4.5 h. The solvent was evaporated and the residue was purified on a Biotage 40S chromatography system, eluting with 0-3% methanol/dichloromethane. Fractions homogeneous for the product were concentrated and the residue held under high vacuum to give (4R,7S)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (420 mg, 58%) as a viscous golden orange oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[O:9][C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)[S:12](=[O:15])(=[O:14])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25]C(C)([O-])C.[K+].CI>CN1C(=O)CCC1.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH:1]1([NH:7][C:8]2[O:9][C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:25])[CH:17]=3)[S:12](=[O:15])(=[O:14])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(O)c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CI
Solvent: O
Product: COc1cccc(C2C(C)(C)OC(NC3CCCCC3)=NS2(=O)=O)c1
Yield: 43.5 %

Procedure:
To a solution of 120 mg of 3-(2-cyclohexylamino-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-5-yl)phenol in 2 ml of NMP were added, at room temperature, 38 mg of potassium tert-butoxide and 97 mg of methyl iodide, and the reaction mixture was stirred at constant temperature for 2.5 hours. The reaction solution was diluted with 60 ml of water, 5 ml of 5% aqueous sodium thiosulfate solution were added, and the mixture was extracted twice with 30 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation, and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fraction was lyophilized. This gave the product (54 mg) with a molecular weight of 366.5 g/mol (C18H26N2O4S); MS (ESI): m/e=367 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH3:26])[CH3:19])[CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Yield: 61 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 3-(dimethylamino) pyrrolidine using standard reductive amination conditions. The resulting crude oil was triturated with diethyl ether and methanol to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-pyrrolidin-3-yl]dimethyl-amine as a solid (61% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 341 as an off white solid (86% yield). NMR (CDCl3, 400 MHz), 1.76-1.82 (1H, m), 2.20-2.10 (1H, m), 2.23 (6H, s), 2.48 (2H, dd, J=7.4 and 8.5), 2.66-2.17 (2H, m), 2.81-2.95 (3H, m), 3.88-3.90 (4H, m), 3.90-3.99 (2H, m), 4.03-4.06 (4H, m), 5.23 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:35][C:36]1[N:41]=[C:40]([CH3:42])[CH:39]=[CH:38][N:37]=1>N1C=CC=CC=1.C1COCC1>[Cl:12][C:3]1[C:4](/[C:5](/[OH:7])=[CH:42]\[C:40]2[CH:39]=[CH:38][N:37]=[C:36]([Cl:35])[N:41]=2)=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][S:21]([C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[F:13])(=[O:23])=[O:22]
Reactant: Cc1ccnc(Cl)n1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: COC(=O)c1cccc(N)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of methyl 3-amino-2-chlorobenzoate (16.3 g, 88 mmol) in pyridine (150 mL) was added 2,5-difluorobenzenesulfonyl chloride (13.0 ml, 97 mmol) dropwise. The solution was stirred at rt overnight. The crude reaction mixture was concentrated by about half, and ˜200 mL of water was added. A red oil precipitated from the mixture. The oil was separated, and crystallized upon standing. The crystals were collected by vacuum filtration, washed with ether, and dried in vacuo to generate 16.8 g (46.4 mmol, 52.8% yield) as a white powder. LC/MS indicates that the product is a ˜2:1 mixture of the desired product and the bis-sulfonamide. The white powder was dissolved in THF (100 mL), and a 1 M solution of LiHMDS in THF (100 mL, 100 mmol) was added. A solution of 2-chloro-4-methylpyrimidine (8.0 g, 62.2 mmol) in THF (10 mL) was added dropwise over 15 minutes. The solution was stirred at 20° C. for an additional 20 minutes, and then the reaction was quenched with MeOH (5 mL). The solvent was removed with a rotary evaporator, and the residue was partitioned between EtOAc and water. The aqueous layer was acidified to pH<9 with saturated aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated to ˜50 mL. The brown solution was passed through a pad of silica gel (eluting with EtOAc) and concentrated to generate the title compound (6.78 g, 14.8 mmol, 16.8% yield) as a yellow powder. MS (ESI): 458.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH2:22][N:35]3[CH2:34][CH2:33][N:32]([C:26]4[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=4[CH3:24])[CH2:37][CH2:36]3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(C)cc4C)CC3)nn2-c2ccccc2)cc1

Procedure:
104 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 1-(2,4-dimethylphenyl)piperazine (50 mg, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.CN(C)C=O.[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:31][C@@H:30]([F:32])[C@H:29]([F:33])[CH2:28]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH2:14]([C:21]1[C:26]([I:1])=[CH:25][CH:24]=[C:23]([N:27]2[CH2:28][C@@H:29]([F:33])[C@H:30]([F:32])[CH2:31]2)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: F[C@@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1F
Solvent: CN(C)C=O
Solvent: O
Product: F[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1F
Reaction time: 8 h
Yield: 100.2 %

Procedure:
94 mg of N-iodosuccinic acid imide was added little by little to 5.0 ml of an N,N-dimethylformamide solution containing 104 mg of 2-benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]pyridine under ice-cooling, followed by stirring overnight as it was. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phase was washed with an aqueous sodium thiosulfate solution, water and brine, and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (10:1), to give 152 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A degassed mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Preparation #1, Step D, 1.70 g, 5.74 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.55 g, 11.48 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.494 g, 0.675 mmol) and K2CO3 (1.58 g, 11.48 mmol) in dioxane (10 mL) and water (2 mL) was heated to reflux for 6 h. The reaction mixture was cooled to ambient temperature and filtered through a pad of Celite®. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 40% EtOAc in petroleum ether) to give 4-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.0 g, 87%) as a pale white solid. LC/MS (Table 1, Method 3) Rt=1.398 min.; MS m/z: 399 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([CH3:12])[CH2:7]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[ClH:1].[ClH:1].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]2[O:10][C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2)[CH2:23][CH2:22]1
Reactant: CN1CC(CCCCCl)OC1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccccc1N1CCN(CCCCC2CN(C)C(=O)O2)CC1
Product: Cl
Yield: 38 %

Procedure:
Following the procedures of Example 1, the title compound is prepared. Thus, a mixture of 5-(4-chlorobutyl)-3-methyl-2-oxazolidinone (5.0 g, 0.0262 mol), 1-(2-methoxyphenyl)piperazine (5.4 g. 0.0279 mol), potassium carbonate (8.5 g, 0.0614 mol), and potassium iodide (0.75 g) in 1-butanol (50 ml) gave 6.8 g of oil which was dissolved in hot methanol and acidified with methanolic hydrogen chloride. Addition of isopropyl ether and isopropanol to the cloud point and cooling gave a solid which was collected by filtration, rinsed with isopropyl ether and light pet ether and dried under high vacuum to give 4.22 g (38% yield), mp 209°-216° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C@H:13]([C:16]([NH2:18])=[O:17])[CH2:14][CH3:15])[C:9](=[O:19])[CH2:8]1)(=O)=O.[I-:20].[Na+]>C1COCC1>[I:20][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:14][CH3:15])[C:16]([NH2:18])=[O:17])[C:9](=[O:19])[CH2:8]1
Reactant: CC[C@@H](C(N)=O)N1CCC(COS(C)(=O)=O)CC1=O
Reactant: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C(N)=O)N1CCC(CI)CC1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 65636364 %

Procedure:
In a 150 ml three necked flask fitted with magnetic stirrer and reflux condenser, under inert atmosphere, 6.88 g (23.5 nmoles) of {1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl}methyl methanesulfonate 24 were dissolved in 86 ml of THF. 3.9 g (25.9 mmoles, 1.1 eq) of sodium iodide were added in one portion and the mixture was brought to reflux. After 5 hours, 780 mg (5.2 mmoles, 0.22 eq) of sodium iodide were added and reflux continued for a total of 10 hours. After cooling down to 0° C., the mixture was filtered, the precipitate washed with THF, the combined organic fractions concentrated to dryness and purified by PrepLC (800 g SiO2, CH2Cl2/MeOH, 95/5) to give 7.21 g of crude compound. It was crystallised from 80 ml ethanol to give 5 g of pure iodide 13, 66% yield.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.ClC(N(C)C)=C(C)C.[NH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].N1C=CC=CC=1>C(Cl)Cl.O>[C:30]([C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[NH:27][C:16]([C:13]1[CH:12]=[CH:11][C:10]2[CH:9]=[C:8]3[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]3[C:15]=2[CH:14]=1)=[O:18])(=[O:31])[NH2:32]
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Reactant: NC(=O)c1ccccc1N
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1ccccc1NC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Reaction time: 5 h
Yield: 26.9 %

Procedure:
To a suspension of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 100 mg, 0.41 mmol) in CH2Cl2 (1.5 mL) is added 1-chloro-N,N,2-trimethylpropenylamine (0.20 mL, 1.43 mmol). The reaction mixture is stirred for 5 h. 2-Aminobenzamide (200 mg, 1.47 mmol) and pyridine (0.12 mL, 1.48 mmol) are added and the reaction mixture is stirred for another 16 h at room temperature. Water (55 mL) is added and the resulting white solid is collected by filtration and purified by flash column chromatography using methanol in CH2Cl2 to afford the title compound (40 mg, 27%). LCMS (ESMS): m/z 363.61 (M+H+).
Reaction SMILES: C(OS([O:7][CH2:8][CH3:9])(=O)=O)C.C(N(CCC)CCC)CC.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](=[CH2:29])C(O)=O.C[C:31](C)=[O:32]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[CH:29][C:31]([O:7][CH2:8][CH3:9])=[O:32]
Reactant: CCOS(=O)(=O)OCC
Reactant: C=C(C(=O)O)c1ccco1
Reactant: CC(C)=O
Agent: CCCN(CCC)CCC
Product: CCOC(=O)C=Cc1ccco1

Procedure:
A mixture of diethylsulphate (57.41 g) and tri-n-propylamine was added dropwise with stirring to a solution of furanylacrylic acid (34.53 g) in acetone (150 ml). When the addition was complete the mixture was refluxed for six hours. The acetone was evaporated at reduced pressure. The resultant oily residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution dried (MgSO4) and the solvent evaporated to yield ethyl 3-(2-furanyl)acrylate (46.7 g) as a brown oil.
Reaction SMILES: [CH3:1][CH:2](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1.[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[N:39]([CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:24])([CH3:25])[CH2:23]3)[N:12]=2)=[CH:7][CH:6]=1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1)N=[N+]=[N-]

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 1-methyl-3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester and sodium azide in DMF. Yield 96 mg (82%).