Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.COC1C=CC2CC(CC(OCC)=O)C3C=CC=CC=3CC=2C=1>CO.C(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2cc(F)ccc21
Agent: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CC1Cc2ccc(O)cc2Cc2cc(F)ccc21

Procedure:
According to the procedure of Preparation 10 (g), except substituting ethyl (±)-10,11-dihydro-7-fluoro3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (±)-10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as a white solid following silica gel chromatography (1% MeOH/CH2Cl2): MS (ES) m/e 315.0 (M+H)+, 332.0 (M+NH4)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:13]([OH:15])=O)([O-:9])=[O:8].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]([F:39])([F:38])[F:37])[NH2:28].CCN(C(C)C)C(C)C>>[N+:7]([C:10]1[CH:11]=[C:12]([C:13]2[O:15][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[N:26]=2)[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([O-:9])=[O:8]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: O=C(O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCCC1

Procedure:
Oxalyl chloride (71 μL; 0.84 mmol; 3 eq.), Intermediate 4 (70 mg; 0.28 mmol; 1 eq.), Intermediate 2 (62 mg; 0.28 mmol, 1 eq.) and DIEA (145 μL; 0.84 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 80/20) followed by precipitation in n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.8) (82 mg, 0.25 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (39 mg, 30%). MS (ISP) 519.0 [(M+H)+]; mp 280-281° C.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([CH:17]=[N:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:28])[NH2:27])[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[NH:27][C:26](=[O:28])[C:20]2[C:19](=[CH:24][C:23]([Cl:25])=[CH:22][CH:21]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)[C@H](C=Nc1cc(Cl)ccc1C(N)=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet, heating mantle, and a water condenser, is charged with 60 mL of THF, 3.70 g (10 mmol) of (R)-{1[(2-carbamoyl-5-chloro-phenylimino)-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (the compound of Formula 201 prepared, e.g., as described in Example 6.1), and 0.46 g (11 mmol) of lithium hydroxide monohydrate. The mixture is heated to reflux and the reaction monitored by TLC (hexanes/ethyl acetate 7:3) by which, after 1 h of refluxing, the reaction is shown to be complete. The mixture is allowed to cool to room temperature and transferred to a round bottom 1-necked flask followed by dilution with 60 mL of water. The stirring mixture is then slowly acidified to pH=5 by adding 1N hydrochloric acid and the THF is removed by rotary evaporation. The white suspension is separated by filtration and dried in high vacuum to afford the title compound of Formula 202, (R)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:20][C:19]([NH2:21])=[CH:18][CH:17]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C.O>CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:20][C:19]([NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nccc(Sc3ccc(N)s3)c2cc1OC
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Sc3ccc(NC(=O)Nc4ccccc4)s3)c2cc1OC
Yield: 48.9 %

Procedure:
5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (89.0 mg, 0.280 mmol) and phenyl isocyanate (36.6 mg, 0.307 mmol) were stirred in dimethylformamide (1 ml) at room temperature for 1 hour. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=50:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (60.0 mg, 0.137 mmol, 48%) as colorless crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1.OS([O-])(=O)=O.[K+]>C(O)C>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21](=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1)[CH:22]([C:8]([C:7]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[CH2:23][CH2:24][CH2:25]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=[N+]([O-])c1cc(Cl)cc2c1CCCC2
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCCc2cc(Cl)cc([N+](=O)[O-])c21
Reaction time: 2 h
Yield: 37.9 %

Procedure:
To a mixture of potassium t-butoxide (79.49 g, 0.708 mol) and diethyl oxalate (105.8 mL, 0.779 mol) in ethanol (140 mL) was added 7-chloro-5-nitrotetralin (14 g, 0.071 mol) at room temperature. The mixture was stirred for 2 h, poured into 10% aqueous KHSO4, and extracted with ethyl acetate (400 mL×2). The combined organic layers were washed successively with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 15:1~6:1 hexane/-ethyl acetate to give 8.39 g of the title compound: 1H NMR (CDCl3) δ7.91 (d, 1H, J=2.1 Hz), 7.45 (d, 1H, J=6.3, 4.0 Hz), 4.41 (m, 2H), 2.82~3.09 (m, 2H), 2.02 (m, 2H), 1.85 (m, 2H), 1.42 (t, 3H, J=7.3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1Br.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[Cl:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Pd]>[Cl:10][C:11]1[CH:12]=[C:13]([C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[F:1])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(Br)c(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc(Cl)c(Cl)c2)c(F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
3-fluoro-4-bromotoluene (50 g, 0.265 mol) and 3,4-dichlorophenylboronic acid (53 g, 0.278 mol) were dissolved in ethanol (970 ml) and sodium carbonate (56.1 g, 0.529 mol) was added. Palladium 10% on charcoal (6.6 g) was added, and the mixture was refluxed for 4 hours under nitrogen atmosphere. The reaction mixture was cooled, filtered and concentrated, isopropyl acetate (250 ml) was added, and then the solution was concentrated again. The residue was dissolved in isopropyl acetate (250 ml) and 1M sodium hydroxide (250 ml). The organic phase was separated, washed with water (125 ml), neutralized with hydrogen chloride 3 M, washed with brine (250 ml), and concentrated. The residue was mixed with acetonitrile/water 1/1 v/v (150 ml), heated to 40° C. to dissolve and then cooled to 0 to 5° C., and stirred for 30 minutes at this temperature. The compound 3′,4′-dichloro-2-fluoro-4-methyl-biphenyl crystallized as a powder.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=O)[CH2:3][CH2:2]1.[NH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1.[BH4-].[Na+].Cl>C1COCC1.C(O)C>[CH3:16][N:12]1[C:11]2[CH2:10][CH2:9][N:8]3[CH:4]([C:15]=2[CH:14]=[CH:13]1)[CH2:3][CH2:2][C:1]3=[O:7]
Reactant: Cn1cccc1CCN
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc2c1CCN1C(=O)CCC21
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A mixture of 110.9 g (1.098 mole) of succinic anhydride and 985 ml of THF was cooled to 10° C. and a solution of 140.53 g (1.098 mole) of 2-(2-aminoethyl)-1-methylpyrrole in 1400 ml of THF was added dropwise over a period of thirty minutes while stirring under an atmosphere of argon, the temperature being maintained at 10 to 15° C. After the addition was complete, stirring was continued an additional one hour and then the solvent removed in vacuo to give a dark-brown, oily residue. The residue was stirred and heated at 175° in an oil bath for three hours under an atmosphere of argon. The residue was distilled on a Kugelrohr apparatus, collecting the product imide at 170° C./0.06 mm, which crystallized to yield an off white solid, mp 116°-121° C. A small sample of the intermediate imide was recrystallized from ethanol to yield a white solid, mp 120°-122° C. A solution of 100 g (0.485 mole) of the above-obtained crude imide was added to 3-1 of 90% aqueous ethanol and the mixture cooled in an ice bath to about 3° C. Sodium borohydride (68.42 g; 1.81 moles) was added and about 25 ml of 2N hydrochloric acid was added dropwise with stirring over a five hour period by means of a metering pump while maintaining a temperature of 0° to 3° C. After the addition was complete (pH=8-9), the reaction was acidified with 1-1 of 2N hydrochloric acid over a period of 1.5 hours while maintaining a temperature of less than 10° C. Stirring (under nitrogen) was continued overnight as the temperature was allowed to gradually warm to ambient, during which time the mixture became a clear, colorless solution. The solvent was partially removed in vacuo using low heat to a final volume of about 800 mls, diluted with 800 mls of water and extracted three times with 300 ml portions of methylene chloride. The combined extracts were washed with 300 ml of water, 300 ml of brine, and dried over anhydrous potassium carbonate. The solvent was removed in vacuo to give 31.07 g of a crude tan solid. The crude solid was recrystallized from about 100 ml of hot EtOAc to give 23.76 g of nearly pure 4,5,7,8,9,9a-hexahydro-3-methyl-3H-pyrrolo[2,3-g]indolizin-7-one, an off-white solid, mp 122°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.Cl[C:14]1[C:15]2[C:22]([CH3:23])=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:20][C:16]=2[N:17]=[CH:18][N:19]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[C:15]3[C:22]([CH3:23])=[C:21]([C:24]([O:26][CH3:27])=[O:25])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)Oc1cc(F)ccc1N
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C)c2c1C

Procedure:
Prepared from 4-fluoro-2-iso-propoxyaniline and methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate in an analogous fashion to that given in general route 1. Yield (0.25 g, 53%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=O)[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.C([O-])(=O)C.[Na+].P(Cl)(Cl)([Cl:35])=O>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([Cl:35])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(Cl)c12

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.13 g) in phosphorus oxychloride (5.0 mL) was heated at 180° C. in a microwave reactor for 15 minutes. The mixture was poured into ice and the pH of the solution adjusted to 3 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent removed under reduced pressure to afford title compound as a beige solid, 0.12 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:14][OH:15]>[Pd]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[N:11]=[C:1]([C:2]1[CH:3]=[CH:4][C:14]([OH:15])=[CH:9][CH:10]=1)[NH:7][C:5]2=[O:6]
Reactant: Cc1cccc(C(N)=O)c1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(O)cc3)nc12

Procedure:
3-Methyl-2-nitrobenzamide (1.20 g, 6.7 mmol) was dissolved in methanol and 10% activated palladium on carbon catalyst (150 mg) was added. The reaction vessel was placed under an atmosphere of hydrogen, at ambient temperature and pressure, until no further hydrogen absorption was observed. The catalyst was removed by filtration of the reaction mixture through a pad of Celite™, which was pre-washed with methanol (150 ml). The solvent was removed under vacuum to give the required product in good yield. The product was used for subsequent reactions without further purification. Yield (0.97 g, 6.4 mmol, 97%), m.p. 145-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[C:22]([N:26]1[C:39]2[C:38](=[O:40])[CH2:37][C:31]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH2:30][C:29]=2[CH:28]=[N:27]1)([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.O.N1(O)C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:22]([N:26]1[C:39]2[C:38](=[O:40])[CH2:37][C:31]3([CH2:36][CH2:35][N:34]([C:15]([C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:8]5[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:21][CH:20]=5)=[CH:19][CH:18]=4)=[O:17])[CH2:33][CH2:32]3)[CH2:30][C:29]=2[CH:28]=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)n1ncc2c1C(=O)CC1(CCNCC1)C2
Reactant: COC(=O)c1ccc(COc2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(COc2ccc(C(=O)N3CCC4(CC3)CC(=O)c3c(cnn3C(C)(C)C)C4)cc2)cc1

Procedure:
A solution of 4-(4-(methoxycarbonyl)benzyloxy)benzoic acid (25 mg, 0.087 mmol), 1-tert-butyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one (26 mg, 0.087 mmol), diisopropylethylamine (53 μL, 0.30 mmol), 1,2,3-benzotriazole-1-ol, monohydrate (14 mg, 0.087 mmol), 4-dimethylaminopyridine (1.1 mg, 0.01 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (19 mg, 0.96 mmol) in dichloromethane (0.2 mL) was heated at 30° C. for 18 hr. The reaction mixture was partitioned between ethyl acetate/aqueous 0.3N hydrochloric acid, the organic phase was dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC to afford methyl 4-((4-(1-tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)phenoxy)methyl)benzoate. HPLC column: Waters Atlantis C18 4.6×50 mm, 5 um, solvent: acetonitrile:water (0.05% TFA); flow rate 2 mL/min; gradient (% organic) start=5%, end=95%, gradient time=4 min, retention time=3.68 min; m/z=530 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[S:7][C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[CH:26]1([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(Cl)Cl>[CH:26]1([CH2:31][C:32]([NH:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]2[S:7][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)=[O:4])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CC1CCCC1)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
2-Amino-N-[4-(4-fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-yl]-2-methyl-propionamide (1 eq), cyclopentyl acetyl chloride (1.05 eq) and triethyl amine (3 eq) were stirred as a solution in DCM (5 mL). Desired product was isolated from reaction mixture by silica gel chromatography. LCMS Method 10 Rt=1.48 (M+1=475.1, M−1=473.1), HRMS; expected=474.2101, found=474.2116. 1H NMR (400 MHz, DMSO-D6) 1.07-1.18 (m, 2H) 1.38 (s, 5H) 1.42-1.51 (m, 2H) 1.52-1.60 (m, 2H) 1.62-1.73 (m, 2H) 2.11 (s, 3H) 2.78-2.88 (m, 4H) 3.69-3.78 (m, 4H) 7.23 (t, J=8.91 Hz, 2H) 8.01 (s, 1H) 8.13 (dd. J=8.59, 5.81 Hz, 2H) 11.45 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]3[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:6]2=3)[CH2:3][CH2:2]1.[ClH:25]>CO.O1CCOCC1>[ClH:25].[CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]3[CH2:14][NH:15][CH2:16][CH2:17][C:6]2=3)[CH2:2][CH2:3]1.[ClH:25]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c3ccccc3n2CC2CC2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc2c(c1)c1c(n2CC2CC2)CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-cyclopropylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (440 mg, 1.35 mmol) was dissolved in methanol (15 mL). 4N HCl in 1,4-dioxan (1.5 mL) was added and the mixture stirred at room temperature overnight. The solution was concentrated in vacuo, azeotroped once with toluene to give 5-cyclopropylmethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride as an off white solid (374 mg, 100% assuming HCl salt).
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[N:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C@H:25]([CH2:46][C:47]4[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[C:50]([NH2:57])=[C:49]([Cl:58])[CH:48]=4)[C:26]([N:28]4[CH2:33][CH2:32][CH:31]([CH:34]5[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43]CC)=[O:42])[CH2:36][CH2:35]5)[CH2:30][CH2:29]4)=[O:27])=[O:23])[CH2:18][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:59]=1>O.C1COCC1.C(#N)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[N:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:46][C:47]4[CH:52]=[C:51]([C:53]([F:56])([F:54])[F:55])[C:50]([NH2:57])=[C:49]([Cl:58])[CH:48]=4)[C:26]([N:28]4[CH2:33][CH2:32][CH:31]([CH:34]5[CH2:39][CH2:38][N:37]([CH2:40][C:41]([OH:43])=[O:42])[CH2:36][CH2:35]5)[CH2:30][CH2:29]4)=[O:27])=[O:23])[CH2:20][CH2:21]3)[CH2:11][CH2:10][C:9]=2[CH:59]=1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5cc(OC)ccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)N3CCC(C4CCN(CC(=O)O)CC4)CC3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 mg (0.04 mmol) LiOH in 1 mL water was added to a solution of 20 mg (0.02 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 1 mL THF and the reaction mixture was stirred overnight at RT. To complete the reaction a solution of 1 mg LiOH in 1 mL water was again added and the mixture was stirred for another 3 h at RT. The solvents were eliminated in a nitrogen stream, the residue was taken up in a mixture of acetonitrile and water and the product was subjected to freeze-drying.
Reaction SMILES: [CH2:1]([S:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCCCCSc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCCCCC)n1

Procedure:
A mixture of 9.5 g. 3-n-pentylthio-1,2,4-triazole, 8.07 g. diallylcarbamoyl chloride, 100 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 68 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-n-pentylthio-1,2,4-triazole, b.p. 135° C./0.1 mm. (90.6% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:10])C=O.[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])CCC1C=CC=CC=1Cl)([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=CC=1C=CC=O>>[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH2:10][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C=O)c1ccccn1
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Agent: O=CC=Cc1ccccc1Cl
Product: CC1CCN(C(=O)C(CCc2ccccn2)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-2-ylpropyl}carbamate is prepared from pyridin-2-yl propionaldehyde (Kitbunnadaj, R. et al. J. Med. Chem, 2004, 47, 2414-2417) in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 3-(2-chlorophenyl)propenal in Example 5.
Reaction SMILES: C(OC([CH:8]1[CH2:14][CH2:13][N:12]2[C:15]([CH3:18])=[CH:16][N:17]=[C:11]2[CH2:10][NH:9]1)=O)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[ClH:19].[CH3:18][C:15]1[N:12]2[CH2:13][CH2:14][CH2:8][NH:9][CH2:10][C:11]2=[N:17][CH:16]=1
Reactant: Cc1cnc2n1CCC(C(=O)OC(C)(C)C)NC2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc2n1CCCNC2

Procedure:
1.89 g 3-methyl-5,6,8,9-tetrahydro-imidazo[1,2-a][1,4]diazepine-7-carboxylic acid tert-butyl ester was stirred in 40 mL 4 mol/L HCl solution in dioxane over night. The mixture was concentrated to give 1.67 g of the desired product. Rt: 0.62 min (method AC), (M+H)+: 152