Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:17])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Cl)c(O)c2c1C
Temperature: -10 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester 0.5 g (2.27 mmol) was added 5 mL of carbon tetrachloride, and the mixture was cooled with an ethanol/ice bath while 1 equivalent of N-chlorosuccinimide was added in small portions. After stirring at −10° C. for 3 h, the reaction mixture was filtered and the filtrate was loaded onto a silica gel column. Chromatography gave 259 mg (48% yield) of 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as an off-white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](F)(F)F)=[CH:27][N:26]=1.ClC1N=CC=CC=1C#[N:39]>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[C@@H:3]1[CH2:23][NH:24][C:25]1[N:26]=[CH:27][CH:28]=[CH:31][C:30]=1[C:29]#[N:39]
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C#N)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-chloronicotinonitrile. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH2:44][CH2:45][O:46]C2CCCCO2)[N:15]=1)=[O:13])[CH3:2].[ClH:53]>CO.O1CCOCC1>[ClH:53].[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH2:44][CH2:45][OH:46])[N:15]=1)=[O:13])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(CCOC2CCCCO2)c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cccc(CC)c1NC(=O)c1nn(CCO)c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2,6-diethylphenyl)-9-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxamide (0.040 g, 0.056 mmol) in MeOH (0.6 mL), 4M HCl in dioxane (0.010 mL) was added. The mixture was stirred at room temperature for 1 h. The organic solvent was evaporated to dryness to give the title compound in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH:23]([OH:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:24][CH:23]2[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1cc(-c2noc3c2CCCC3O)ccc1-n1cnc(C)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2noc3c2CCCC3Oc2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Yield: 43.2 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-ol (48 mg, 0.149 mmol) in THF (1.0 mL) was added 4-flurophenol (23 mg, 0.2 mmol), Ph3P (58 mg, 0.22 mmol) and DEAD (39 mg, 0.22 mmol). The reaction mixture was stirred over night at 50° C. The reaction mixture cooled, diluted with EtOAc, washed with water and brine, dried over MgSO4 and concentrated. The crude product was purified by preparative TLC using 5% MeOH in DCM as solvent to afford 27 mg of the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH2:14][N:13]([C:22]([C:21]4[C:20]([N:27]5[N:31]=[CH:30][CH:29]=[N:28]5)=[N:19][C:18]([CH3:17])=[CH:26][CH:25]=4)=[O:23])[CH2:12][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccc(C)nc4-n4nccn4)CC3C2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pale yellow solution of 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (Intermediate 23) (50 mg, 0.23 mmol) in 2 mL of DMF was added 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid (Intermediate 70) (51 mg, 0.25 mmol) followed by HATU (131 mg, 0.34 mmol) and DIPEA (0.118 mL, 0.69 mmol). The resulting solution was allowed to stir at room temp for 1 h and turned progressively more intense yellow as the reaction continued. The reaction was monitored via LCMS and quenched with H2O once starting materials we no longer observed. The resulting biphasic mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried with Na2SO4 and conc. into a pale yellow oil under reduced pressure. The yellow residue was purified via FCC using 5-50% 2M NH3/MeOH in DCM. Minor impurities remained so the material was further purified via HPLC 0-99% CH3N to give the desired product. MS (ESI) mass calcd. for C21H24N8O, 404.47; m/z found 405.3 [M+H]+. 1H NMR (400 MHz, CDCl3) 7.80 (s, 2H), 7.72 (d, J=7.7 Hz, 1H), 7.29-7.24 (m, 1H), 6.30 (s, 1H), 3.90-3.80 (m, 2H), 3.73-3.63 (m, 2H), 3.59 (dd, J=11.6, 5.3 Hz, 1H), 3.47 (dd, J=11.6, 3.7 Hz, 1H), 3.33 (s, 1H), 3.00 (ddd, J=38.4, 21.7, 7.2 Hz, 3H), 2.68 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: CCCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Reactant: Oc1cccc(N2CCNCC2)c1
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C
Yield: 52 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21](O)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)=[O:7])=[CH:13][CH:12]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: NC1CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N3-Cyclopropyl-N4′-cyclopropylmethyl-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide was synthesised from {4′-[(cyclopropylmethylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}carboxylic acid and cyclopropylamine using method A. NMR: δH [2H6]-DMSO 8.62, (1H, t), 8.43, (1H, d), 7.93, (2H, d), 7.74, (1H, dd), 7.68, (1H, d), 7.46, (2H, d), 7.38, (1H, d), 3.16, (2H, t), 2.83, (1H, m), 2.26, (3H, s), 1.04, (1H, m), 0.67, (2H, m), 0.54, (2H, m), 0.43, (2H, m), 0.24, (2H, m). LCMS: retention time 2.89 min, MH+349.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:16]O>>[SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(S)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Mercaptobenzoic acid (10.0 g) was suspended in methanol (310 mL), added with sulfuric acid (0.3 mL), and stirred for 24 hours under reflux with heating. After cooling to room temperature, the solvent was evaporated under reduced pressure and water was added to residues. After adjusting to pH 8 by using a saturated aqueous solution of sodium hydrogen carbonate, it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After distilling the solvent under reduced pressure, the residues were purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[F:12].ClC1C=C(C(OO)=[O:21])C=CC=1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:21])=[CH:9]2)=[CH:4][C:3]=1[F:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cc2ccncc2cc1Cl
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
25 g (137.7 mmol) of 7-Chloro-6-fluoro-isoquinoline (3) were in dissolved in 500 ml of dichloromethane. At room temperature 50.9 g (206.5 mmol) of 3-Chloro-benzene-carboperoxoic acid (70%) were added and the mixture was stirred at room temperature until complete conversion is achieved. For workup, the precipitate was filtered off and washed with dichloromethane. The filtrate was washed twice with NaHCO3-solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried with MgSO4 and evaporated. The so obtained solid material (18.4 g) was used without further purification. Rt=0.87 min (Method C). Detected mass: 198.1/200.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1CCOCC1>C1COCC1>[O:18]=[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: NCC(=O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)c1cc2cc(Cl)cnc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 50 mg, 0.25 mmol), 2-aminoacetophenone hydrochloride (48 mg, 0.28 mmol) and DMTMM (85 mg, 0.31 mmol) were dissolved in THF (5 mL) and 4-methylmorpholine (31 μL, 0.28 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and EtOAc (3×20 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19) to give the title compound. m/z (ES+)=314 [M+H]+; RT=3.47 min.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][C:6](OCC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[CH:5][CH2:6][OH:7]
Reactant: CCOC(=O)C=Cc1ccccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCC=Cc1ccccc1Br
Temperature: 25 °C
Yield: 61 %

Procedure:
Ethyl o-bromocinnamate (66.3 g; 260 mM) was dissolved in 750 ml of anhydrous toluene under nitrogen in a three-neck round bottom flask equipped with addition funnel and condensor. A toluene solution of diisobutylaluminum hydride (520 mM; 1.53M) was transferred via canula to the addition funnel and then added dropwise to the reaction mixture, which had been chilled to -78°. After the addition was completed the reaction was warmed to ambient temperature over a 1.5 hour period and quenched by the dropwise addition of 50 ml of water. Some cooling was required. The resulting emulsion was added to 640 ml of 2N aqueous hydrochloric acid. After partitioning the slightly acidic (pH 5) aqueous layer was extracted twice with ether. The combined organic fractions were dried (MgSO4), filtered (fritted funnel), and evaporated to afford an oil. The oil was chromatographed in two portions on the Waters Prep 500 equipped with two cartridges eluting with a total of two gallons of 35% ethyl acetate in hexane. This produced 33.8 g (61% yield) of o-bromocinnamylalcohol. NMR (CDCl3): δ 6.8-7.8 (m; 5H); 6.0-6.6 (AB; 1H); 4.2-4.4 (brd.; 2H); 2-2.6 (brs; 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[N:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(OCC)(=O)C.[H][H]>C(O)C.[Pt](=O)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:4]=1
Reactant: N#Cc1cccnc1-c1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cccnc1-c1cc(N)ccc1F

Procedure:
A solution of 2-(2-fluoro-5-nitrophenyl)nicotinonitrile (1.2 g, 4.9 mmol) and platinum(IV) oxide in ethanol (50 ml) with ethyl acetate (50 ml) was reduced under 40 psi hydrogen for 30 minutes then filtered and the solvent removed to give an orange oil. Purification by chromatography (silica gel, 1% MeOH/CH2Cl2) gave 2-(5-amino-2-fluorophenyl)-nicotinonitrile as an orange oil: 1H NMR (360 MHz, CDCl3) δ 8.88 (1H, dd, J 2, 5 Hz), 8.07 (1H, dd, J 2, 8 Hz), 7.42 (1H, dd, J 5, 8 Hz), 7.04 (1H, t, J 9 Hz), 6.85 (1H, dd, J 3, 6 Hz), 6.76-6.81 (1H, m); MS (ES+) m/z 214 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([Cl:9])[Cl:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([N:12]([CH2:13][CH3:14])[PH:7]([Cl:9])([Cl:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: CCNCC
Reactant: ClP(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: CCN(CC)[PH](Cl)(Cl)c1ccccc1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
Phenyldichlorophosphine (4.47 g, 25.0 mmol) was dissolved in 80 mL of toluene and then cooled to 0° C. under N2. Diethylamine (3.65 g, 50.0 mmol) was added dropwise and the resulting reaction mixture was allowed to warm-up to room temperature (ca. 20° C.) overnight (ca. 12 hrs). Reaction was then filtered and the liquid phase was concentrated to give 5.25 g (97% yield) of N,N-diethyl-phenylphosphoramidous chloride.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].[OH-:14].[NH4+]>C1COCC1>[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]([NH2:9])=[O:14]
Reactant: CC(C)C(C)(N)C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(C)(N)C(N)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To concentrated sulfuric acid (29.7 ml), cooled with stirring in an ice-acetone cooling bath, is added 11.8 g (-)-2-amino-2,3-dimethylbutyronitrile with [α]D25 =7.31° (c=0.0368 g/ml THF) at such a rate that the temperature does not go above 25° C. After the addition, the temperature of the reaction mixture is slowly raised to 100° C. and held at that temperature for one hour. After cooling the mixture in an ice-acetone bath, 85 ml concentrated ammonium hydroxide is added at such a rate that the temperature does not exceed 75° C. The mixture is extracted five times with methylene chloride, the combined extracts dried and concentrated. This gives 11.95 g of white solid, mp 79°-81° C. and [α]D25 =+57.43° (c=0.0213 g/ml THF). This solid is recrystallized from methylene chloride-hexane to give 11.2 g of (+)-2-amino-2,3-dimethylbutyramide, mp 81°-82° C. [ α]D25 =+59.38° (c=0.0162 g/ml THF).
Reaction SMILES: [F:1][C:2]1([F:18])C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:19][O:20][CH:21](OC)[O:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:20][C:21]1([O:22][CH3:23])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3][C:2]1([F:1])[F:18]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1(F)F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2)CC1(F)F
Temperature: 45 °C
Yield: 84 %

Procedure:
The mixture of 4-(3,3-difluoro-4-oxo-piperidin-1-yl)-nitrobenzene (25 mmol), trimethylorthoformate (51 mmol), p-toluene-sulphonic acid monohydrate (27 mmol) in methanol was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 84% yield.
Reaction SMILES: [Br:1][C:2]([Br:13])([Br:12])[CH2:3][C:4]1(Cl)[C:7]([CH3:9])([CH3:8])[CH2:6][C:5]1=[O:10].[ClH:14]>C(O)C>[Br:1][C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6]([Cl:14])[C:5]1=[O:10]
Reactant: CC1(C)CC(=O)C1(Cl)CC(Br)(Br)Br
Reactant: Cl
Solvent: CCO
Product: CC1(C)C(Cl)C(=O)C1CC(Br)(Br)Br
Temperature: 80 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
22.8 g (0.054 mole) of 2-(2',2',2'-tribromoethyl)-2-chloro-3,3-dimethylcyclobutan-1-on is dissolved in 220 ml of absolute ethanol saturated with hydrogen chloride and the solution is stirred for 5 hours at 80° C. Then solvent is evaporated until the volume of the reaction mixture is reduced to one third of the starting volume and, after addition of water, the mixture is extracted with ether. The etheral extract is washed at first with saturated sodium chloride solution and subsequently with sodium bicarbonate solution and thereafter dried over sodium sulphate. The residue obtained after evaporation of the ether is purified by chromatography on silica gel using toluene as eluent. After combination of the pure fractions and evaporation of the solvent there is obtained 17.1 g (75% of theory) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-chloro-cyclobutane-1-one, melting point 87°-89° C.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)[CH2:9][CH3:10].S(Cl)([Cl:22])=O>N1C=CC=CC=1>[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([Cl:22])=[O:19])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Toluene (1,000 ml) was added to trans-4-propylcyclohexanecarboxylic acid (1) (500.0 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was heated to 50° C. Pyridine (0.70 ml) and thionyl chloride (360.0 g) were then added, and the stirring was continued for 3 hours. The unreacted thionyl chloride and the toluene were distilled off at atmospheric pressure. The residue was distilled under reduced pressure (83° C., 3 mmHg) to give trans-4-propylcyclohexanecarboxylic acid chloride (2) (531.7 g) in 98% yield.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N+:11]([O-:13])[CH2:12][C:6]2=[N:5][N:4]=1.[CH3:25][NH:26][CH3:27]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:8]2[N:7]3[C:3]([CH2:2][N:26]([CH3:27])[CH3:25])=[N:4][N:5]=[C:6]3[CH2:12][N+:11]([O-:13])=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[CH:20]=1
Reactant: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2-n2c(CBr)nnc2C1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=[N+]([O-])C2

Procedure:
To a suspension of 2.0 parts of 1-bromomethyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 5-oxide in 20 volume parts of dimethylformamide is added 5 volume parts of 40 weight % aqueous solution of dimethylamine under stirring, and the resulting solution is stirred for 30 minutes at room temperature. After removing the solvent, the crystalline residue is recrystallized from ethyl alcohol to give 8-chloro-1-dimethylaminomethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 5-oxide as colorless prisms melting at 217° to 219° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:9][C:10]([CH3:34])=[C:11]([C:30]([O:32][CH3:33])=[O:31])[CH:12]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:13]=1[C:14]([O:16]CCC#N)=[O:15])=[N+:2]=[N-:3].[OH-].[K+]>CC(C)=O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[NH:9][C:10]([CH3:34])=[C:11]([C:30]([O:32][CH3:33])=[O:31])[CH:12]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[C:13]=1[C:14]([OH:16])=[O:15])=[N+:2]=[N-:3]
Reactant: COC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)O)C1c1ccc([N+](=O)[O-])cc1
Yield: 61.2 %

Procedure:
A solution of 2-(4-azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(4-nitrophenyl)pyridine (1.38 g,. 2.95 mmol) in 10 ml acetone was treated with 15 ml 1N KOH solution at 0° C. for 1 hr. The acetone was removed in vacuo and the aqueous layer was acidified to pH=3 by 2N hydrochloric acid, the resulting yellow precipitate was collected by filtration, washed with 10 ml of cold water and dried in vacuo to yield 750 mg (61% yield) of 2-(4-azidobutyl)-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(4-nitrophenyl)pyridine-3-carboxylic acid as a yellow powder.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)C.O.[OH-].[Na+]>[C:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)NCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCNc2ccccc21

Procedure:
A solution of 0.186 mole (25 g) of 1,2,3,4-tetrahydroquinoxaline is dissolved in 250 ml of ethanol and 17.6 ml of acetic anhydride is added dropwise with stirring. The solution is then diluted with 750 ml of water and basified with 1N sodium hydroxide. The solution is extracted with chloroform, the organic extracts are dried and then evaporated to provide the solid product, 1-acetyl-1,2,3,4-tetrahydroquinoxaline.
Reaction SMILES: [BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH3:36])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[S:28][C:29]=1[CH:30]=[O:31]>C1COCC1>[C:19]1([CH3:36])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][OH:31]
Reactant: Cc1ccccc1-c1c(C=O)sc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1c(CO)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Tetrabutylammonium borohydride (nBu4NBH4) (800 mg, 3.10 mmol) was added at RT to a solution of 3-o-tolylbenzo[b]thiophene-2-carbaldehyde (2.07 mmol) in THF (10 mL) and IMS (1 mL) and the mixture was stirred at RT for 1 h. The reaction mixture was then quenched by addition of MeOH and volatiles were removed under reduced pressure. The resulting residues was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) affording the title compound as an oil (432 mg, 82% over 2 steps). LCMS: RT 3.74 min [M-OH]+ 237.1.