Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)N(C)CCC1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].Cl[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH:42][CH3:43])=[O:41])[CH:35]=1.CC([O-])(C)C.[K+]>O.CN(C=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH:42][CH3:43])=[O:41])[CH:35]=3)=[CH:23][CH:22]=2)=[CH:13][C:12]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=C(CCc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
To a mixture of DMPU (0.7 mL) and DMF (2.8 mL) was added N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(4-hydroxyphenyl)propanamide (600 mg, 1.75 mmol) and 4-chloro-N-methylpyridine-2-carboxamide (prepared as described in Bankston, D. et al. Organic Process Research and Development 2002, 6, 777-781; 328 mg, 1.92 mmol). To this solution was added KOt-Bu (590 mg, 5.25 mmol). The reaction mixture was stirred at 100° C. for 18 h and then cooled to rt, diluted with water and extracted with EtOAc and DCM. The combined organic solutions were washed with water and brine, dried over Na2SO4, filtered and concentrated to give a brown oil. Purification by column chromatography provided 100 mg of a colorless solid. 1H NMR (300 MHz, CD3OD) δ: 10.11 (br s, 0.34H), 8.41 (d, J=5.6 Hz, 1H), 8.07 (br d, J=2.2 Hz, 1H), 7.74 (br dd, J1=8.7 Hz, J2=2.1 Hz, 1H), 7.48-7.51 (m, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 2H), 6.98 (dd, J1=5.6 Hz, J2=2.5 Hz, 1H), 3.34 (s, 0.84H), 3.04 (t, J=7.5 Hz), 2.92 (s, 3H), and 2.71 (t, J=7.5 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([N:16]([CH2:21][C:22]2[CH:32]=[CH:31][C:25]3[O:26][CH2:27][CH2:28][CH2:29][O:30][C:24]=3[CH:23]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl>O1CCOCC1>[O:26]1[C:25]2[CH:31]=[CH:32][C:22]([CH2:21][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([C@@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[O:15])=[CH:23][C:24]=2[O:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8.79 g of (−)-4-benzyl-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylmorpholine-2-carboxamide and 50 mL of 4N HCl in dioxane was stirred for 3 hrs at room temperature, then concentrated under reduced pressure. The residue was partitioned between 3×50 mL of chloroform and 20 mL of saturated sodium carbonate, dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave the product as a resin: MS (m+1)=349.3; H NMR (400 MHz, CDCl3) 7.3-6.7 (complex m, 5H), 4.6 (br d, 1H), 6.8-6.7 (m, 2H), 4.4 (d, 1H), 4.2 (m, 4H), 4.15 (q, 1H), 4.08 (br d, 1H), 3.95 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.0 (dd, 1H), 2.2 (m, 1H), 2.0 (m, 1H) 1.45 (2×s, 9H), 0.9 (dd, 6H).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[C:11](=[O:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[C:1]([NH:9][CH:10]([CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:11]([OH:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(=O)C(Cc1cccnc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CN(CC(O)C(Cc1cccnc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The product from part (d) is treated with sodium borohydride according to the procedure of Example 1(f) to yield (±)-1-[[[3-(benzoylamino)-2-hydroxy-4-(3-pyridinyl)butyl]methylamino]carbonyl]-L-proline.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C(Cl)Cl>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:22](=[O:23])[NH:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: CCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCNC(=O)Oc1ccc2oc3ccccc3c2c1
Yield: 105.7 %

Procedure:
A solution of 2-hydroxydibenzofuran (5.0 g, 27 mmol), hexyl isocyanate (4.1 g, 32 mmol) and triethylamine (3.0 mL, 22 mmol) in 75 mL of methylene chloride was stirred under nitrogen at room temperature overnight. The reaction was extracted with 1N HCl. The organic solution was dried (MgSO4) and the solvent removed under reduced pressure to give 8.89 g of an off-white solid. Recrystallization of the solid from isopropanol gave 5.48 g (65%) of the title compound as an off-white crystalline solid, mp 109°-110° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[Br:15][C:16]1[C:21]([NH2:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([S:11]([NH:22][C:21]2[C:16]([Br:15])=[N:17][CH:18]=[C:19]([Cl:23])[CH:20]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: CC(=O)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 1.6 g (6.32 mmol) of 3-acetyl-4-chloro-benzenesulfonyl chloride and 1.3 g (6.28 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 8 mL pyridine using procedure x. Yield: 1.3 g of a white solid. LC-MSD, m/z for C13H9BrCl2N2O3S [M+H]+=422.8, 424.8, 426.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:20])=[N:11][N:12]([CH3:19])[C:13]=1[C:14](OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C-:28]#[N:29].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH3:20])=[N:11][N:12]([CH3:19])[C:13]=1[CH2:14][C:28]#[N:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(C)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(C)c(CC#N)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a 15 ml solution of ethyl 4-benzyloxy-1,3-dimethylpyrazol-5-carboxylate (2.5 g, 9.1 mmol) in anhydrous tetrahydrofuran (hereinafter, referred to as THF) was added lithium aluminium hydride (0.2 g, 5.3 mmol) under ice-cooling. After stirring at room temperature for one hour, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate, and the extract was successively washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. To the residue (2 g) was added toluene (5 ml) and thionyl chloride (2 g) and the resulting mixture was heated under reflux for one hour. After low boiling substances were evaporated, the residue was combined with ethyl acetate. The mixture was successively washed with, water, aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. To a 5 ml solution of the residue in dimethyl sulfoxide (hereinafter, referred to as DMSO) was added sodium cyanide (0.43 g, 8.8 mmol) and the mixture was stirred at room temperature and left to stand overnight. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate, and the extract was successively washed with water, and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel (eluent; ethyl acetate/n-hexane=1:2) to obtain (4-benzyloxy-1,3-dimethylpyrazol-5-yl)acetonitrile (1.6 g, 6.6 mmol, 73%).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:11]=[C:10]([CH3:20])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:4])[CH3:2].[OH-].[Na+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:9][C:7](=[O:8])[C:6]2[C:10]([CH3:20])=[CH:11][C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:13][C:5]=2[S:3]([CH2:1][CH3:2])=[O:4])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 70 %

Procedure:
To a solution of 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzamide (0.17 g, 0.57 mmol) in benzene-tetrahydrofuran (1:1) (8 ml) are added tetrabutylammonium hydrogensulfate (0.02 g, 0.057 mmol) and 15% sodium hydroxide solution (5 ml) at RT. 4-Chlorobenzyl bromide (0.083 g, 0.40 mmol) in tetrahydrofuran (0.5 ml) is added and the reaction mixture is slowly heated to 70° C. The reaction mixture is stirred at 70° C. for additional 25 min. After completion of the reaction (monitored by TLC), the organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 20% acetone/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzamide (example 6) (0.12 g, 0.28 mmol, 50%). [M+H]+ 421.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][C:15]([CH3:17])=[CH:16][C:6]=3[C:5]=2[CH:4]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:4]1[C:5]2[C:6]3[CH:16]=[C:15]([CH3:17])[S:14][C:7]=3[C:8](=[O:13])[NH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1
Product: COc1ccc2[nH]c(=O)c3sc(C)cc3c2c1Br
Yield: 40 %

Procedure:
Following Step 4 from General Procedure A, 8-methoxy-2-methylthieno[2,3-c]quinolin-4(5H)-one (1.4 g, 5.7 mmol) was reacted with N-bromosuccinimide (1.2 g, 6.9 mmol) to afford the desired product (740 mg, 40%) as a brown solid: ESI MS m/z 325 [C13H10BrNO2S+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[NH:14][C:11]2=[N:12][CH:13]=1)=[O:6])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:38][CH:39]([CH2:43][O:44][CH3:45])[CH2:40][O:41][CH3:42]>CN(C=O)C>[CH:1]([O:4][C:5](=[O:6])[NH:7][C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:21])[NH:38][CH:39]([CH2:43][O:44][CH3:45])[CH2:40][O:41][CH3:42])[CH:18]=3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(C(=O)O)c3)nc2c1
Reactant: COCC(N)COC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COCC(COC)NC(=O)c1cccc(-c2nc3cc(NC(=O)OC(C)C)cnc3[nH]2)c1
Reaction time: 4 h

Procedure:
25 mg (0.07 mmol) of the acid from example 11-1 in 1 ml dry DMF were treated with 18 mg (0.11 mmol) 1,1′-carbonyl-diimidazole at room temperature for 2 hrs. 13 mg (0.11 mmol) 2-amino-1,3-dimethoxypropan were added and stirring was continued for 4 hrs. The solvent was removed under vacuum, the residue dissolved in dichloromethane and washed with aqueous sodium carbonate solution. The dichloromethane phase was evaporated and the residue purified by chromatography on silica in dichloromethane/methanol mixtures.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][O:10][C:9]3=[N:13][C:14]([NH2:16])=[N:15][N:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH:19]=1.C(Cl)Cl>C(Cl)Cl.CO>[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][CH:27]([NH:16][C:14]3[N:13]=[C:9]4[O:10][CH2:11][CH2:12][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]4[N:15]=3)[CH2:26][CH2:25]2)[CH:19]=1
Reactant: Nc1nc2n(n1)C(c1ccccc1)CCO2
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2CCC(Nc3nc4n(n3)C(c3ccccc3)CCO4)CC2)ncn1

Procedure:
Prepared in analogy to example 1h, starting from 7-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[5,1-b][1,3]oxazin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a light yellow solid (yield: 17%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 392.3 (100) [(M+H)+].
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11].[Li]CCCC>C1COCC1>[C:3]([C:4]1[C:5]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])#[CH:2]
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine (2.677 gm, 5.63 mmol) in dry THF (25 ml) was cooled to -78° C. and treated with n-BuLi (1.6M in hexane, 7.75 ml, 12.4 mmol) over a 1 minute period. After stirring at -78° C. for one hours, the deep green solution was quenched with saturated NH4Cl, warmed to room temperature, diluted with H2O, and extracted once with Et2O. The Et2O extract was washed with brine, dried (Na2SO4), filtered and stripped to give a yellow solid. The solid was recrystallized from a minimum amount of hot hexane to afford analytically pure 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as yellow crystals (1.572 gm, 89%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CC(C)=O>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 80.8 %

Procedure:
To a mixture of 300.0 mg (2.203 mmol) 4-hydroxyacetophenone and 305 mg (2.207 mmol) potassium carbonate in 15 ml acetone was added 868.7 mg (3.304 mmol) 4-(trifluoromethoxy)benzylbromide dropwise and heated under reflux for 1 d. The solvent was evaporated and to the residue was added ethyl acetate. The organic phase was washed with 1M aqueous HCl solution and water, dried over magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate/n-heptane 1:2) to yield 552 mg (1.779 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethanone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:17])=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([Cl:17])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 91 %

Procedure:
A mixture of 50 g. of 3-(3-nitrophenyl)propenoic acid, 24.54 ml. of thionyl chloride and 300 ml. of benzene were heated under reflux for 2.5 hours. The cooled solution was filtered and then it was evaporated in vacuo. The residue was recrystallized from carbon tetrachloride, to give 49.9 g. (91% yield) of the title compound, m.p. 81°-83.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:21][CH2:20][N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[S:11][N:10]=[N:9][C:8]=2[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=2
Reactant: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1c2ncccc2-c2nnsc2-c2cccnc21
Yield: 73.1 %

Procedure:
To a solution of 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (0.700 g) in tetrahydrofuran (5 mL) was added potassium bistrimethylsilylamide (0.5M in toluene, 3.5 mL). After 10 minutes the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 8-ethyl-(1, 2, 3)thiadiazolo[4',5':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.453 g). mp 194-196° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH3:13]>CC(C)=O.CO>[NH2:13][C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: N
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 216 h
Yield: 148.1 %

Procedure:
Performed in duplicate on identical scales in two pressure vessels, methyl 2,5-dichloronicotinate (4.5 g, 22 mmol) was dissolved in ammonia solution (250 mL, 0.5 M in 1,4-dioxane; 0.125 mol). The pressure vessels were sealed and heated at (85±5)° C. for 9 days. The two reaction mixtures were allowed to cool to room temperature, then combined and concentrated under reduced pressure to yield a white solid. Dissolution of the solid in 1:1 acetone-MeOH (˜500 mL), followed by adsorption onto silica gel (25 g) and then purification by flash column chromatography (25:10:1 hexane-CH2Cl2-Et2O), gave 6.08 g (75%) of methyl 2-amino-5-chloronicotinate.
Reaction SMILES: [CH3:1][N:2]([CH3:42])[CH2:3][CH2:4][CH2:5][S:6]([N:9]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:10][C:11](=[O:37])[C@@H:12]([C@@H:17]([C:27](=[O:36])[NH:28][O:29]C1CCCCO1)[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:8])=[O:7].O.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1>CO>[C:44]1([CH3:54])[CH:45]=[CH:46][C:47]([S:50]([OH:53])(=[O:51])=[O:52])=[CH:48][CH:49]=1.[CH3:42][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][S:6]([N:9]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:10][C:11](=[O:37])[C@@H:12]([C@@H:17]([C:27](=[O:36])[NH:28][OH:29])[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:8])=[O:7]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCN(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCN(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.2 %

Procedure:
A solution of 0.184 g of (E)-2′-[3-(dimethylamino)propylsulphonyl]-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 4 ml of methanol was treated with 0.069 g of p-toluene-sulphonic acid monohydrate. The mixture was stirred for 3.5 hours at room temperature and evaporated. Trituration of the residue with diethyl ether gave 0.19 g of (E)-2′-[3-(dimethylamino)propylsulphonyl]-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide p-toluenesulphonate in the form of an off-white solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:12][Si:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][O:8][CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
A mixture of 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (8.7 g), tert-butyl 4-hydroxyphenylcarbamate (6.4 g) and cesium carbonate (20 g) in DMF (60 mL) was stirred at 60° C. for 24 h. After cooling to room temperature, to the mixture was added SiO2, the mixture was evaporated, and then the residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give tert-butyl {4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}carbamate (14 g) as brown oil.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1>[I:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: ICCCCCCI
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ICCCCCCn1c2ccccc2c2ccccc21
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of carbazole (0.5 g, 2.99 mmoles) in THF (6 mL), NaH (0.25 g, 6 mmoles) was slowly added. The mixture was stirred for 1 hour giving a solution. The resulting solution was introduced under nitrogen in a dropping funnel and slowly added in 10 minutes to a solution of 1,6-diiodo hexane (3 ml, 18 mmoles) in THF (2 mL). The reaction mixture stirred for 2 hours at room temperature, it was quenched with water and ice and THF was evaporated under reduced pressure. The mixture was extracted with ethyl ether (3×5 mL) and the organic phases were collected and combined, dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by chromatography (from n-hexane to n-hexane:CH2Cl2 10:1). Yield: 83%. Rf=0.55 (cyclohexane/dichloromethane 3/1).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15](=O)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:15]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:24])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)CCC(C)(C)c2cc(NC(=O)Cc3ccccc3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(NCCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A solution of phenylacetic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (7) (790 mg, 2.46 mmole) in 20 mL diethyl ether (ether) was treated with 400 mg of lithium aluminium hydride (LAH) and heated at reflux for 90 minutes. After cooling the reaction flask to 0° C., the reaction mixture was quenched by successive addition of 0.4 mL water, 0.4 mL of 15% aqueous sodium hydroxide solution and 1.2 mL water. The mixture was stirred at room temperature for 30 minutes and MgSO4 was added. After filtration, the mixture was concentrated in vacuo, to provide a pale yellow oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes), yielding 619 mg (82%) of phenethyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (9) as a pale yellow oil.