Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>CS(C)=O>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COc1ccccc1OCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyanophenol (742 g, 6.23 mol) is dissolved in dimethyl sulfoxide (7.30 L) and to this solution is added powdered anhydrous potassium carbonate (883 g, 6.30 mol), potassium iodide (1.05 kg, 6.30 mol) and finally 1-(5-chloropentoxy)-2-methoxybenzene (1.44 kg, 6.29 mol). This suspension is heated at 80°-82° C. for 7 hours and the heating bath is then removed. After stirring overnight at room temperature, the mixture is poured onto cold water (29 L) and the product precipitates. This mixture is then extracted with ethyl acetate (3×20 L). The organic extracts are washed with potassium hydroxide solution (0.50N, 4×8 L), brine (2×10 L), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a yellow oil which crystallizes on standing. This is then dissolved in 2-propanol (5.6 L) with warming and the resulting solution is filtered gravimetrically, washing the funnel with 1.2 L of hot 2-propanol. The combined filtrate is cooled to 10° C. in an ice bath and the solid mass is broken up and filtered. The filter cake is washed with 2-propanol (2×800 mL), dried in vacuo to give 4-[5-(2-methoxyphenoxy)pentoxy]benzonitrile, m.p. 66°-68° C. which is >99.5% pure by glc analysis.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:7]=[C:8]([N:13]=[C:14]=[S:15])[CH:9]=[CH:10][C:11]=1[Cl:12]>C(O)C>[C:2]([NH:3][C:14]([NH:13][C:8]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=1)=[S:15])#[N:1]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
The suspension of monosodium cyanamide (1.6 g, 24.5 mmol) in absolute ethanol (50 mL) was slowly treated with 3,4-dichlorophenylisothiocyanate (5.0 g, 24.5 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (5.0 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[CH:14]=1.O>CN(C=O)C>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:14]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NC(=O)N=C2NC(=O)CN2C)c1
Temperature: 55 °C
Yield: 38 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8, and 1.6 g (12.8 mM) of 4,6-dimethyl-2-aminopyridine in 50 ml of anhydrous DMF was heated at 55° C. for 8 hrs., cooled, and poured into 200 ml water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.3 g of the above urea as a light yellow solid, m.p. 192°-193° C.
Reaction SMILES: [OH-].[K+].Cl.[NH2:4][CH2:5][CH2:6][SH:7].Cl.Cl[CH2:10][C:11]1[N:12]=[C:13]([CH2:16][OH:17])[S:14][CH:15]=1>C(O)(C)C>[NH2:4][CH2:5][CH2:6][S:7][CH2:10][C:11]1[N:12]=[C:13]([CH2:16][OH:17])[S:14][CH:15]=1
Reactant: NCCS
Reactant: OCc1nc(CCl)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: NCCSCc1csc(CO)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (10.6 g) was added to a suspension of 6.82 g of cysteamine hydrochloride and 10.0 g of 4-chloromethyl-2-hydroxymethylthiazole hydrochloride in 100 ml isopropanol. The resulting suspension was stirred an room temperature for 2 hours and filtered through a pad of celite to remove insoluble inorganics and concentrated under reduced pressure. The residue was taken up in dichloromethane and filtered through a pad of celite and concentrated under reduced pressure. The oil (12.54 g) represents a quantitative yield of 4-[[(2-aminoethyl)thio]methyl]-2-hydroxymethylthiazole contaminated only with inorganic salts.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([O:3][CH3:4])=[O:2].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=[O:7])[CH2:5][C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CC(=O)Cl
Reactant: CNc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)N(C)c1ccccc1
Reaction time: 0.07 h

Procedure:
The carbomethoxy acetyl chloride mixture is cooled in an ice-salt bath to -5 to 0° and N-methyl aniline (55.64 g, 0.52 mol) in methylene chloride (200 ml) is added at a rate so as to maintain the temperature of the reaction mixture between -5 to 0°. The addition is performed using an addition funnel and can normally be carried out over a 3-5 min time period to control the slight exotherm. Pyridine (66.36 g, 0.84 mol) in methylene chloride (200 ml) is then added to the above mixture. The addition rate is adjusted so as to keep the temperature of the reaction between -5 to 0° during the addition. The addition is performed using an addition funnel and can normally be carried out over a 3-5 min time period to control the slight exotherm. After the addition is complete (as measured by HPLC) the reaction is quenched by pouring the reaction mixture into water (500 ml) and stirring continued for 30 min. The reaction is equilibrated and the methylene chloride layer separated. Additional methylene chloride (400-500 ml) is added and the methylene chloride mixture is washed successively with hydrochloric acid (1N, 2×300 ml), saturated sodium bicarbonate solution (2×300 ml), saline (1×600 ml) and the methylene chloride mixture dried through anhydrous sodium sulfate. Concentration of the mixture under reduced pressure at 40-45° gives the title compound, HPLC (Nucleosil column; acetonitrile/water, 45/55, 1 ml/min, UV=229 nm; Retention times for N-methyl-N-phenyl-α-carbomethoxyacetamide~6.0 min; N-methyl aniline~11.0-12.0 min.
Reaction SMILES: N.[Li].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15]CC2C=CC=CC=2)[CH2:12][C@H:11]1[CH2:23][O:24][CH3:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(C)(C)C>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]1[CH2:23][O:24][CH3:25])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: N
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
In a flask purged with ammonia gas, about 40 mL of liquid ammonia is collected with ammonia condenser at −78° C. To the liquid ammonia is added portionwise lithium metal (46 mmol; 320 mg) at the same temperature. To the deep blue solution is added a solution of (2S,4R)-4-benzyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (9.2 mmol; 3.1 g) and tert-butanol (18.4 mmol; 1.36 g) in THF (15 mL). After stirring for 2 hours, the reaction mixture is quenched with MeOH, and then warmed to ambient temperature. The mixture is diluted with water, and then aqueous 1M HCl is added to reach pH 8-9. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give (2S,4R)-4-hydroxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[CH3:23]C1C=C(C=CC=1)C(Cl)=O>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[C:17]([CH3:23])[CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CCN)c1

Procedure:
This compound was prepared analogously to Intermediate A by replacing benzoyl chloride (step 2) with 3-methylbenzoyl chloride (commercial).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[CH3:33][O:34][CH2:35][CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1>>[OH:31][CH2:30][CH2:29][N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:11][N:8]([CH:39]3[CH2:40][CH2:41][CH:36]([CH2:35][O:34][CH3:33])[CH2:37][CH2:38]3)[CH2:9]2)=[O:32])=[N:17]1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COCC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: COCC1CCC(N2CC(NC(=O)CNc3nn(CCO)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 74, Step A) and 4-methoxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3([OH:25])[CH2:24][NH:23][CH2:22]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([N:23]1[CH2:24][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:32])[CH3:33])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)([OH:25])[CH2:22]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](c1ccc(C#CC2(O)CNC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CC(=O)N1CC(O)(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)C1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((3-hydroxyazetidin-3-yl)ethynyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and acetic anhydride following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.27 min, m/z=491, 433; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 1.97 (s, 3H), 2.15-2.45 (5H), 2.84 (m, 1H), 4.20 (d, 1H), 4.36 (m, 2h), 4.44 (d, 1H), 5.65 (q, 1H), 6.88 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.[NH2:13][OH:14].C(N(CC)CC)C>C(O)C>[OH:14][NH:13][C:10](=[NH:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: NO
Reactant: COc1ccc(CC#N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CC(=N)NO)cc1

Procedure:
A mixture of (4-methoxyphenyl)acetonitrile (2.00 g, 14 mmol) and hydroxylamine hydrochloride (1.94 g, 28 mmol) in ethanol (25 mL) was treated with triethylamine (4.4 mL) and heated at reflux for 16 hours after which the solvent was evaporated under reduced pressure. Sodium carbonate solution (10%, 100 mL) was added and the solution extracted with ethyl acetate (150 mL). The organic extract was dried, filtered and evaporated under reduced pressure to give a green solid which was purified by recrystallization from ethyl acetate/hexane to give 1.43 g (57%) of (Via) as pale green prisms. mp 163-170° C. (lit.14 108-109°). MS m/z 181 (M+1)+
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([C:31]#[N:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C2(C#N)CCCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C2(C#N)CCCCC2)cc1

Procedure:
2-(7-Cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyanocyclohexyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing (7-cyano-1H-benzimidazol-1-yl)acetic acid (216 mg, 1.08 mmol) prepared according to scheme 3, 1-[4-(1-aminoethyl)phenyl]cyclohexanecarbonitrile (246 mg, 1.08 mmol) prepared according to scheme 11, Et3N (328 mg, 3.24 mmol, 0.452 mL) and HATU (411 mg, 1.08 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (443 mg, 1.08 mmol, quantitative). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.22-1.36 (m, 1H) 1.39 (d, J=6.84 Hz, 3H) 1.53-1.68 (m, 2H) 1.68-1.77 (m, 1H) 1.77-1.89 (m, 4H) 1.98-2.08 (m, 2H) 4.88-5.02 (m, 1H) 5.24 (dd, J=24.61, 17.77 Hz, 2H) 7.35 (t, J=7.91 Hz, 1H) 7.40 (d, J=8.40 Hz, 2 H) 7.46 (d, J=8.40 Hz, 2H) 7.72 (d, J=7.62 Hz, 1H) 8.01 (dd, J=8.20, 0.78 Hz, 1H) 8.35 (s, 1 H) 8.85 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 412.0. found: 412.3.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C([N:16]2[CH2:20][CH2:19][CH:18]3[CH2:21][N:22]([C:24]4[C:25]5[S:33][C:32]6[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=6[C:26]=5[N:27]=[C:28]([NH2:30])[N:29]=4)[CH2:23][CH:17]23)C)C=CC=CC=1>[OH-].[OH-].[Pd+2].CCO>[NH:16]1[CH2:20][CH2:19][C@@H:18]2[CH2:21][N:22]([C:24]3[C:25]4[S:33][C:32]5[CH2:34][CH2:35][CH2:36][CH2:37][C:31]=5[C:26]=4[N:27]=[C:28]([NH2:30])[N:29]=3)[CH2:23][C@H:17]12
Reactant: CC(c1ccccc1)N1CCC2CN(c3nc(N)nc4c5c(sc34)CCCC5)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2C[C@H]3CCN[C@H]3C2)c2sc3c(c2n1)CCCC3
Reaction time: 36 h
Yield: 95.1 %

Procedure:
A 90 mL parr shaker was charged with 4-[1-(1-phenyl-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl]-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine trifluoroacetate (synthesized by route described in Example 2, Steps A-E; 0.20 g, 0.4 mmol), Pd(OH)2/C (30% by weight, 0.06 g) and EtOH (3.7 mL). The mixture was submitted to 60 psi H2 with shaking for 36 h. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated to afford the desired compound (0.12 g). MS: 316.1. 1H NMR (400 MHz, CD3OD) 8 ppm 4.47-4.29 (m, 2H), 4.25-4.07 (m, 2H), 3.91-3.80 (m, 1H), 3.54-3.38 (m, 3H), 2.97-2.84 (m, 2H), 2.69-2.61 (m, 2H), 2.41-2.29 (m, 1H), 2.14-2.02 (m, 1H), 2.02-1.86 (m, 4H).
Reaction SMILES: [O:1]1[N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:4]2[CH2:3][C@H:2]1[CH2:19][N:20]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[O:1]1[N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:4]2[CH2:3][C@H:2]1[CH2:19][NH2:20]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H]2c3ccccc3Cc3ccccc3N2O1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@@H]1C[C@H]2c3ccccc3Cc3ccccc3N2O1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.3 %

Procedure:
A mixture of (±)-cis-2-[(2,3,3a,8-tetrahydrodibenz[c,f]isoxazolo[2,3-a]azepin-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (4 g), prepared following the procedure of example 1, and hydrazine hydrate (0.5 ml) in ethanol (80 ml) was stirred at 80° C. for 4 hours. The precipitate was filtered off and purified by open column chromatography over silica gel (eluent: CH2Cl2 /2-propanone 8/2). The pure fractions were collected and evaporated. The residue (1.6 g) was convened into the oxalic acid salt (1:1) in C2H5OH at room temperature. The residue (0.8 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97.5/2.5 to 95/5). The pure fractions were collected and evaporated, yielding 0.6 g (22%) of (±)-cis-2,3,3a,8-tetrahydrodibenz[c,f]isoxazolo-[2,3-a]azepine-2-methanamine (comp. 9).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[CH3:13][NH:14][C:15](=[S:18])[NH:16][NH2:17]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[N:17][NH:16][C:15](=[S:18])[NH:14][CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CNC(=S)NN
Solvent: CCO
Product: CNC(=S)NN=C(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of 4-chlorobutyrophenone (7.6 mL, 48 mmol) and 4-methylthiosemicarbazide (5.0 g, 48 mmol) in 300 mL of ethanol under a nitrogen atmosphere was warmed to dissolve all the solids and then allowed to stir at room temperature overnight. The solvent was removed under reduced pressure to give 13.0 g of a light yellow solid. Recrystallization of the solid form ethanol gave 7.25 g (57%) of the title compound as a white solid, mp 94-96° C.
Reaction SMILES: [NH2:1][C:2]([CH3:36])([CH2:27][O:28]CC1C=CC=CC=1)[CH2:3][NH:4][C:5]([C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[C:10]2=[N:9][C:8]=1[CH3:26])=[O:6].C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:2]([CH3:36])([CH2:27][OH:28])[CH2:3][NH:4][C:5]([C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[C:10]2=[N:9][C:8]=1[CH3:26])=[O:6]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC(C)(N)COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC(C)(N)CO

Procedure:
Under argon, 800 mg (1.57 mmol) of rac-N-[2-amino-3-(benzyloxy)-2-methylpropyl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide Example 263 were initially charged in 16.2 ml of ethanol, and 167 mg of palladium on activated carbon (10%) and 4.77 ml (47.1 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux for 18 h and then applied to Celite and purified by silica gel chromatography (mobile phase: dichloromethane/methanol 10/1, dichloromethane/2N ammonia in methanol 10/1). This gave 366 mg of the target compound (56% of theory; purity 97%).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:16]([O:18]CC)=O)=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1.COC1C=CC(C([NH2:29])=O)=CC=1.ClC(C(C)=O)C(OCC)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>C(O)CCC.C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:16]([NH2:29])=[O:18])=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Reactant: COc1ccc(C(N)=O)cc1
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: N
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCCCO
Solvent: CCO
Product: COc1ccc(-c2nc(C)c(C(N)=O)s2)cc1
Yield: 69 %

Procedure:
Into a mixed solvent of 50 ml of aqueous 28% ammonia and 450 ml of ethanol, 13.9 g of ethyl 2-(4-methoxyphenyl)-4-methylthiazole-5-carboxylate which had been prepared by heating a mixture of p-methoxybenzamide, ethyl α-chloroacetoacetate, phosphorus pentasulfide and n-butyl alcohol under a reflux for 5 hours was dissolved. Then, in a similar manner as in Example 3 the object was obtained as colourless aciculate melting at 179.5° to 180.5° C. in an amount of 8.6 g corresponding to the yield of 69%.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][NH:26][CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1([CH2:42][C:43](O)=[O:44])[CH:41]=[CH:40][N:39]=[N:38]1>>[CH2:1]([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:23]([NH:25][N:26]([CH2:27][CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:43](=[O:44])[CH2:42][N:37]1[CH:41]=[CH:40][N:39]=[N:38]1)=[O:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1ccnn1
Reactant: CCC(CC)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Product: CCC(CC)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1)C(=O)Cn1ccnn1

Procedure:
In a manner analogous to that described in Example 8 from (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methylvalerohydrazide and using 1,2,3-triazole-1-acetic acid in place of N-tert-butoxycarbonyl-β-alanine there was obtained (E)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-(2-ethylbutyl)-4-methyl-2′-[2-(1H-1,2,3-triazol-1-yl)acetyl]valerohydrazide in the form of a gum.
Reaction SMILES: CO[CH:3](OC)/[C:4](=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[CH3:15])/[C:5]#[N:6].CC1C(C)=CC=CC=1CC(C(OC)OC)C#N.O.[NH2:36][NH2:37].Cl>CO.C(O)C.[Pd]>[CH3:15][C:9]1[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:4]1[C:5]([NH2:6])=[N:36][NH:37][CH:3]=1
Reactant: NN
Reactant: COC(OC)/C(C#N)=C/c1cccc(C)c1C
Agent: [Pd]
Agent: COC(OC)C(C#N)Cc1cccc(C)c1C
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: Cc1cccc(Cc2c[nH]nc2N)c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The suspension of (2E)-2-[bis(methyloxy)methyl]-3-(2,3-dimethylphenyl)-2-propenenitrile (1.55 g, 9.2 mmol) and 10% Pd/C (36 mg, 0.33 mmol) in methanol (25 mL) was hydrogenated using the Parr shaker (23° C., 50 bar) overnight. The catalyst was removed by filtration. Concentration of filtrate gave desire product. (0.26 g, 17%). To a solution of 2-[(2,3-dimethylphenyl)methyl]-3,3-bis(methyloxy)propanenitrile (257 mg, 1.1 mmol) and hydrazine monohydrate (55.1 mg, 1.1 mmol) in ethanol (15 ml) stirred under nitrogen at room temperature was added a solution of 36% HCl (558 mg, 5.51 mmol) dropwise. The reaction mixture was stirred at 100° C. for overnight. Reaction mixture was concentrated and dissolved with ethyl acetate (30 mL) and water (10 mL). pH of aqueous layer was adjusted to 8˜9. Two layers were separated. Organic layer was washed with brine (5 mL), dried and concentrated. Crude product was purified with silica gel column (0-10 methanol/DCM). Product was obtained and used in next step. (191 mg, 86%); LC/MS: MS (ES+) m/e 202 (MH+).
Reaction SMILES: [C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[CH:17]=2)=[C:6]1[OH:33])([CH3:4])([CH3:3])[CH3:2].C(C1[N:42](CC2C=CC(F)=C(C)C=2)[C:41](=O)C(C2NC3C=CC(NS(C)(=O)=O)=CC=3S(=O)(=O)C=2)=C1O)(C)(C)C>>[C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[C:17]=2[C:41]#[N:42])=[C:6]1[OH:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(CN2C(=O)C(C3=CS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)C2C(C)(C)C)ccc1F
Reactant: CC(C)(C)C1C(O)=C(C2=CS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)N1CCC1CC1
Product: CC(C)(C)C1C(O)=C(C2=C(C#N)S(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)N1CCC1CC1

Procedure:
N-{3-[5-tert-Butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-2-cyano-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide was prepared from N-{3-[5-tert-butyl-1-(2-cyclopropyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (15c, R3=c-C3H5—(CH2)2) to afford 78 mg (49%) of I-27: LCMS RT 2.40 min, M+H.