Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ICC>C1COCC1.CN1CCCN(C)C1=O>[C:9]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([CH2:1][CH3:2])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (6.5 mL, 2.0 M in heptane/THF/ethylbenzene) in THF (25.0 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5.0 mL) was added methyl 3-(4-(benzyloxy)phenyl)propanoate 23.1 (3.00 g, 11 mmol) in THF (10 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.5 mL) at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes and then iodoethane (1.0 mL, 13 mmol) in THF (5.0 mL) was added. The reaction mixture was stirred at the same temperature for 20 minutes. The reaction was then stirred at room temperature for 16 hours. The reaction was quenched with water (30.0 mL), and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with brine (2×25 mL), and dried with Na2SO4. The residue was purified by silica gel column (eluent with hexane/EtOAc; 85/15) to give the title compound 32.1. MS ESI (pos.) m/e: 299.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH2:49])[CH3:48])[CH:41]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:31]([O:35][C:36](=[O:50])[NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][C@H:47]([NH:49][CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:48])[CH:41]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: C[C@@H](N)Cc1cccc(CCNC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Cc1cccc(CCNC(=O)OC(C)(C)C)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 63.5 %

Procedure:
A stirred solution of 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethyl-silanyloxy)ethyl]-1H-quinolin-2-one (3.14 g, 6.43 mmol); {2-[3-((R)-2-aminopropyl)-phenyl]ethyl}carbamic acid tert-butyl ester (1.79 g, 6.43 mmol) and triethylamine (1.08 mL, 7.72 mmol) in DMF (21.0 mL) was microwaved (300 watts) at 80° C. for 15 h. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give the title compound (2.8 g, 63% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH2:17])[N:11]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[C:3]=1[C:28]#[N:29].[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32].O>CS(C)=O.C(N(C(C)C)CC)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][S:33]([CH2:30][CH2:31][CH3:32])(=[O:35])=[O:34])[N:11]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)[C:3]=1[C:28]#[N:29]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN)n3)nc(N)c2C#N)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)NCc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(NC(C)=O)cc3)n2)n1
Reaction time: 0.5 h

Procedure:
To a suspension of 0.1 g of the compound of Example 32 in 5 mL of DMSO, 0.25 mL of diisopropylethylamine was added, and 0.04 mL of 1-propanesulfonyl chloride was added dropwise under stirring. After 30 minutes, water was added to the reaction mixture, and the resulting crystal was filtrated, and dried under reduced pressure to give 80 mg of N-[4-(6-amino-5-cyano-2-{6-[(propane-1-sulfonylamino)methyl]pyridin-2-ylmethylsulfanyl}pyrimidin-4-yl)phenyl]acetamide as a white powder.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]#[N:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+].CN(C)C=[O:33]>O>[O:33]=[C:14]([O:13][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([Cl:11])[C:8]=1[Cl:12])[CH2:2][C:3]([CH3:23])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:4]2)[C:15]1[NH:16][N:26]=[N:25][N:24]=1
Reactant: CN(C)C=O
Reactant: CC1(c2ccccc2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CC1(c2ccccc2)Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1

Procedure:
(1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetonitrile (4.87 g., 0.014 mole), sodium azide (1.09 g., 0.0168 mole), ammonium chloride (0.90 g., 0.0168 mole) and dimethylformamide (30 ml.) are heated at 80° C. for 21/2 hrs. The reaction mixture is poured into water (500 ml.), the solution filtered and acidified with 6N hydrochloric acid to precipitate 2.60 g. of 5-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxymethyl)tetrazole which melts at 227°-229° C. after crystallization from ethanol.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C:6]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[N:26]1([C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[C:6]3[CH2:7][C@H:2]([NH:1][S:38]([C:35]4[CH:34]=[CH:33][C:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:37][CH:36]=4)(=[O:39])=[O:40])[CH2:3][O:4][C:5]=3[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NS(=O)(=O)c2ccc(N4CCOCC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (120 mg, 0.485 mmol) in anhydrous methylene chloride (10 mL) were added triethylamine (81 μL, 0.582 mmol) and 4-(4-morpholinyl)benzenesulfonyl chloride (140 mg, 0.534 mmol; described in: Galliani, G. Eur. Pat. Appl. EP 335, 758, 1989, Chem. Abstr. 1990, 112, 98374d [125393-22-8]). The reaction mixture was stirred at room temperature for 4 h, washed with a 2 M NH3 solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (eluent: chloroform/ethanol, 90:10+0.5% conc. NH3) affording 141 mg (61% yield) of the title compound as a white solid: mp sinters >100° C.; [α]22D +10° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 472 (56, M+).
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)=[CH:19][CH:18]=1>C(O)(C)C>[ClH:16].[ClH:1].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=[C:6]2[CH2:5][CH2:4][CH2:3][N:2]=[C:7]2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:19][CH:18]=1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: [Cl-]
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Solvent: CC(C)O
Product: Cl
Product: Clc1ccc(Oc2cccc(C=C3CCCN=C3c3cccnc3)c2)cc1
Temperature: 80 °C
Yield: 74.1 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (162 mg, 0.64 mmol) was suspended in a reaction vessel with i-propanol (12 mL). 3-(4-chlorophenoxy)benzaldehyde (225 mg, 0.97 mmol) was then added and the reaction vessel sealed. The reaction was heated to 80° C. overnight and then cooled to room temperature. The precipitate was recovered by vacuum filtration, washed with a 20% i-propanol in hexane solution then dried under vacuum giving 161 mg (56%) of a tan-colored solid. LC-MS: RT=6.22 min, [M+H]+=375.1.
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11]([OH:13])=O)[CH2:10][C:5]=2[NH:4][CH:3]=1.S(Cl)(Cl)=O.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[OH:18][C:19]1[CH:20]=[C:21]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([C:11]([CH:9]3[CH2:8][CH2:7][C:6]4[N:2]=[CH:3][NH:4][C:5]=4[CH2:10]3)=[O:13])[CH2:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Oc1cccc(C2CNc3ccccc32)c1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(C1CCc2nc[nH]c2C1)N1CC(c2cccc(O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
A mixture of 1.99 g of hydrochloride (racemic form) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid, 0.15 ml of dimethyl formamide and 20 ml of thionyl chloride was refluxed for three hours. The resultant reaction solution was distilled to dryness under a reduced pressure. The residue consequently formed was added to a solution of 2.07 g of (+)-3-(3-hydroxyphenyl)indoline in 75 ml of tetrahydrofuran. This reaction solution was stirred at room temperature for 12 hours, then weakly alkalinized by addition of the saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then distilled. The residue was refined by silica gel column chromatography to obtain 2.00 g of 5-[{3-(3-hydroxyphenyl)indolin-1-ylcarbonyl}]-4,5,6,7-tetrahydrobenzimidazole (56.8%) as an epimer mixture.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][N:13]=2)[CH2:8]1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>ClCCl.C(N(CC)CC)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.[Cu]I>[Cl:2][C:3]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:14][N:13]=2)[CH2:8]1
Reactant: Clc1ccc(CN[C@H]2CCN(c3ccc(I)cn3)C2)c(Cl)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
Dissolve (S)-(2,4-dichlorobenzyl)-[1-(5-iodopyridin-2-yl)-pyrrolidin-3-yl]-amine hydrochloride (250 mg, 0.52 mmol) in dichloromethane (15 mL) and triethylamine (10 mL). Add trans-dichlorobis(triphenylphosphine)palladium (II) (24 mg, 0.034 mmol), copper (I) iodide (6 mg, 0.032 mmol) and (trimethylsilyl)acetylene (370 μL, 2.62 mmol). Stir the mixture at room temperature for 1 h, filter through a pad of Celite®, concentrate and chromatograph on silica gel, eluting with a gradient of 20:80 to 1:1 ethyl acetate:hexanes, to give (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-3-yl]-amine as a yellow oil (190 mg, 88%). MS (ES): m/z=418 [M+H].
Reaction SMILES: [H-].[K+].CN(C)C=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][C:10]=1[OH:16].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.O>[CH2:17]([O:16][C:10]1[CH:11]=[C:12]([OH:13])[CH:14]=[CH:15][C:9]=1[Br:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(Br)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 0° C. slurry of 1.7 g. (42.5 mmoles) of potassium hydride in 35 ml. of N,N-dimethylformamide is slowly added a solution of 7.22 g. (38.2 mmoles) of 4-bromoresorcinol. The resultant mixture is stirred for 30 minutes and then 4.54 ml. (38.2 mmoles) of benzyl bromide is slowly added. The reaction mixture is stirred 3 hours longer at 0° C. and then added to 200 ml. of cold water and 200 ml. of ether. The ether extract is washed twice with 200 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil is purified via column chromatography on 400 g. of silica gel eluted with 25% ether-pentane to yield (in order of elution) 2.2 g. (16%) of 2,4-dibenzyloxybromobenzene, 0.21 g. (2%) of 5-benzyloxy-2-bromophenol and 3.52 g. (33%) of 3-benzyloxy-4-bromophenol.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=[CH:3]1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[CH3:12][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][CH:5]=[C:6]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)c1cccc(=O)n1C
Yield: 28.5 %

Procedure:
In Example 22, 0.4006 g (2.611 mmol) of methyl 6-oxo-1,6-dihydropyridine-2-carboxylate and 0.4006 g (2.899 mmol) of potassium carbonate were combined in a 25 mL RBF. 1 mL of DMSO followed by 4 mL (64.25 mmol) of methyl iodide was added and the reaction refluxed for 4 hours. The solvent was removed under reduced pressure and the resulting oil was extracted with hot hexanes (8×25 mL), the extracts were combined and solvent removed to yield a yellow oil. Recrystallization from hexanes yielded the product as white/yellow crystals (0.1245 g, 28.52%). Melting Point: 56-57° C. IR: (Nujol) 3437.61, 1731.13, 1652.94, 1590.77, 1457.45, 1443.48, 1379.43, 1265.53, 1218.08, 1156.78, 1086.06, 900.89, 825.45, 817.06, 765.03, 755.48, 722.85 cm−1. 1H NMR: (500 MHz, CDCl3) 3.67 (s, 3H), 3.91 (s, 3H), 6.71 (dd, J=1.2, 9.1 Hz, 1H), 6.74 (dd, J=1.2, 6.8 Hz, 1H), 7.29 (dd, J=6.7, 9.1 Hz, 1H). 13C NMR: (126 MHz, CDCl3) 33.40, 52.90, 110.42, 124.46, 137.21, 138.21, 162.45, 162.70.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[N:7]([NH2:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH:20](N)=[NH:21].C(OC(O)C)C.C(Cl)(Cl)Cl>CO>[C:1]([C:5]1[CH:9]=[C:8]2[N:7]([CH:6]=1)[N:15]=[CH:20][N:21]=[C:10]2[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)cn1N
Reactant: N=CN
Agent: CCOC(C)O
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(O)ncnn2c1
Yield: 25.6 %

Procedure:
Ethyl 3-tert-Butyl-1-aminopyrrole-5-carboxylate (1.00 g, 4.76 mmol, 1 eq), formamidine acetate (1.46 g, 14.3 mmol, 3 eq.) and ethoxyethanol (10 mL) were mixed and refluxed for 3 hours. The solvent was stripped and then restripped from chloroform (3×) to yield a solid. This solid was stirred in 5 mL MeOH, filtered, and the collected solids rinsed with Et2O and dried to yield 233 mg of a white solid as product. LCMS found: (M+H)++=191.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].[H-].[Na+].I[CH3:30]>CN(C=O)C.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:30])[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:17]=1)#[N:2]
Reactant: CI
Reactant: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc(N(C)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) is treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min. Iodomethane (0.03 mL, 0.53 mmol) is added, and the mixture is stirred at room temperature for 18 h. The reaction mixture is then diluted with H2O, and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Purification by flash chromatography over silica gel (EtOAc/CH2Cl2, 0-1%) gives 60 mg (45%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([O:16]C)=[O:15])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:10]=2[CH3:28])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:10]=2[CH3:28])=[CH:7][CH:8]=1
Reactant: COC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2sc(C(=O)O)c(-c3ccc(S(N)(=O)=O)cc3)c2C)cc1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Methyl 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 7d, 3.02 g, 7.24 mmol) was suspended in ethanol (50 ml) and NaOH (1.44 g, 36.2 mmol) in water 10 ml was added at 25° C. The reaction mixture was heated at 50-55° C. under stirring for 2 hr. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Water, 50 ml was added to the residue so obtained and the mixture was cooled using icebath. Aqueous hydrochloric acid (10%) was then added to the mixture to bring the pH to between 5 and 6. The mixture was then extracted with ethyl acetate (2×75 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a product (2.83 g, 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[CH3:13][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:12])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C)c1ccc(CC(=O)N(C)[C@@H]2CCc3c(CC(=O)O)c4ccccc4n3C2)cc1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from [4-(dimethylamino)phenyl]acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 420.
Reaction SMILES: [NH:1]([C:3](=[O:23])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]=[C:39]=S)=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[O:23][C:3]([C:4]([NH:6][C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]5)=[N:11][CH:12]=4)=[O:5])=[N:1][N:2]=3)=[CH:34][CH:33]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)C1CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Reactant: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Product: COC(=O)C1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(Cl)cc5)cc4)o3)cn2)CC1

Procedure:
Prepared using the procedures described above for Example 631 except starting from methyl 1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)piperidine-4-carboxylate (Intermediate 83) and 1-chloro-4-(4-isothiocyanatophenoxy)benzene. 1H NMR δ 1.51-1.61 (m, 2H), 1.86-1.91 (m, 2H), 2.59-2.66 (m, 1H), 2.91-2.98 (m, 2H), 3.63 (s, 3H), 4.14-4.19 (m, 2H), 6.87 (d, 1H), 7.00 (d, 2H), 7.13 (d, 2H), 7.41 (d, 2H), 7.64 (d, 2H), 7.90 (d, 1H), 8.47 (s, 1H), 10.88 (s, 1H), 10.97 (s, 1H); MS m/e MH+ 549.
Reaction SMILES: [C:1]([N:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([N:8]1[CH2:9][CH2:10][O:11][C:23](=[O:25])[O:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N(CCO)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(=O)OCC1

Procedure:
The procedure of Example 1 was followed using N-boc diethanolamine (3 g, 14.6 mmol), triethylamine (4.1 mL, 29.2 mmol), dry dichloromethane (100 mL) and triphosgene (1.4 g, 4.9 mmol). The filtrate was concentrated yielding only oligomeric compounds.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].Cl.CN(C)CCCN=C=NCC.[C:20](O)(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a stirring solution of 1.71 g (14.75 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 2.22 ML (17.2 mmol) of triethylamine and 592 mg (4.85 mmol) of 4-dimethylaminopyridine at 0° C. Next, 3.38 g (17.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4.96 g (17.7 mmol) of linoleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is recrystallized from pentane at -78° C. to give a solid which melts upon warming to room temperature giving 1.67 g (30%) of 4-hydroxy-3-[(Z,Z)-1-oxo-9,12-octadecadienyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:28][O:29][CH3:30]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:28][O:29][CH3:30])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1-c1ccc(O)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(5-bromo-3-nitropyridin-2-yl)phenol (280 mg, 0.95 mmol) and DIPEA (360 mmg, 2.85 mmol) in 5 mL of dry DCM at 0° C. was added dropwise chloro(methoxy)methane (210 mg, 1.9 mmol). The reaction was warmed to rt and stifling was continued for 3 h and the diluted with EtOAc (30 mL), washed with water (3×30 mL) and dried over MgSO4. Solvent was removed under reduced pressure and the residue was purified by silica chromatography (EtOAc in hexane, 5% to 35%) to afford 5-bromo-2-(4-(methoxymethoxy)phenyl)-3-nitropyridine as a yellow wax (260 mg, 80%). MS (ESI) m/z [M+H]+339, 341.