Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)c4ccccc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Benzoylbenzoic acid (0.50 g, 2.2 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 15 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (150 mg, 0.60 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (140 mg, 0.57 mmol) and triethylamine (120 μL, 0.86 mmol) in methylene chloride (30 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 120 mg (48%) of the title compound as white crystals: mp 194-195° C.; [α]21D -51° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 453 (2, M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)(F)c1cc(-c2ccc(Br)cc2)nc2c(-c3ccncc3)cnn12
Yield: 37.7 %

Procedure:
Reaction of 1-(4-bromo-phenyl)-4,4,4-trifluoro-butane-1,3-dione (148 mg, 0.5 mmol), prepared from commercially available 4-bromo-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (79 mg, 38%). MS (ISP) 421.2 [(M+H)+]; mp 289° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[O-:10][C:11]#[N:12].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:11]([NH2:12])=[O:10]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
A solution of 2-chloro-5-methylaniline (10 g, 70.6 mmol) and potassium cyanate (14.3 g, 176 mmol) in a mixture of acetic acid (340 mL) and water (34 mL) was stirred at room temperature during 4 hours. The solvent was evaporated and the residue taken into a mixture of CH2Cl2 and an aqueous saturated solution of NaHCO3. The precipitate was filtered, washed with dichloromethane and dried under vacuum to give 12.6 g (97%) of intermediate 7.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:25]([NH2:28])[CH:26]=[CH2:27].O>C(OCC)(=O)C>[CH2:25]([NH:28]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH:26]=[CH2:27]
Reactant: C=CCN
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 43 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and a solution of one part by volume of allylamine in 2 parts by volume of water with a yield of 43% of theory. M.p. 104°-106° C. (ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=2[NH2:14])[CH2:4][CH2:3]1.O.[N:21]#[C:22]Br.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=3[N:14]=[C:22]2[NH2:21])[CH2:6][CH2:7]1
Reactant: N#CBr
Reactant: CN1CCN(CCCNc2ccc(Cl)cc2N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(CCCn2c(N)nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 2-[3-(4-methyl-1-piperazinyl)propylamino]-5-chloroaniline (70 g., 0.248 mole) in 350 ml. of water and 150 ml. ethanol was added, with stirring, 59.0 g. (0.557 mole) of cyanogen bromide in portions over 1 hour. The temperature was maintained at 40°-50° C. After the addition was completed the mixture was allowed to cool to room temperature and stirred overnight. After pouring into 1500 ml. ice water and making strongly alkaline with 20% NaOH, the precipitated solid was collected on a Buchner funnel, washed with water and dried in the vacuum oven to obtain 45.0 g. (59% yield) of crude 1-[3-(4-methyl-1-piperazinyl)propyl]-2-amino-5-chlorobenzimidazole, m.p. 223°-227° C. A portion was recrystallized from acetone as colorless needles, m.p. 228°-229.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.Cl.[CH3:21][NH:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CS(C)=O>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:23][N:22]([CH3:21])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(Cl)ncn2)c1
Reactant: CNCC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)ncn2)c1
Temperature: 110 °C
Yield: 93.6 %

Procedure:
To a solution of 3-(6-chloro-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (0.4 g, 1.44 mmol) in DMSO (3 mL), N-methylneopentylamine hydrochloride (0.4 g, 2.9 mmol) and DIEA (0.5 mL, 2.9 mmol) were added. The resulting solution was heated at 110° C. for 4 days. The product was purified by silica gel column chromatography using ethyl acetate as eluent to afford the product (0.46 g, yield 99%). MS (m/z): 342 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34]Cl)=[CH:33][C:28]=2[O:27][CH2:26]1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC4OCOC=4C=3)N=2)CC1)=O)(C)(C)C>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][N:14]3[C:15]4[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=4[C:12]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)=[N:13]3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc4c(c3)OCO4)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc4c(c3)OCO4)c3c2CCNCC3)cc1
Yield: 45.8 %

Procedure:
The title compound (0.035 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using benzo[1,3]dioxol-5-ylmethyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 2-benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H20ClN3O2, 381.12; found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.32 (m, 4H), 6.67-6.65 (m, 1H), 6.54-6.61 (m, 2H), 5.81 (s, 2H), 5.16 (s, 2H), 2.81-2.79 (m, 4H), 2.76-2.74 (m, 2H), 2.68-2.66 (m, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18](=O)[C:19]1[CH:20]=[N:21][N:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]=1[C:24]([F:27])([F:26])[F:25])(=O)OC.O.[NH2:36][NH2:37]>>[C:28]1([N:22]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:19]([C:18]3[N:37]=[N:36][C:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=4[CH:17]=3)[CH:20]=[N:21]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CCCCCCC1=O
Reactant: COP(=O)(CC(=O)c1cnn(-c2ccccc2)c1C(F)(F)F)OC
Reactant: NN
Solvent: O
Product: FC(F)(F)c1c(-c2cc3c(nn2)CCCCCC3)cnn1-c1ccccc1

Procedure:
light yellow solid. MS (EI): 372.3 (M+). Prepared from cyclooctane-1,2-dione, [2-oxo-2-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]2)[C:22]1=[O:41]>>[NH2:8][C:6]1[S:7][C:3]([CH2:2][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:33]4=[CH:34][C:35]5[O:39][CH2:38][O:37][C:36]=5[CH:40]=[C:32]4[O:31][CH2:30]3)[C:22]2=[O:41])=[C:4]([C:9]([F:12])([F:11])[F:10])[N:5]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Nc1nc(C(F)(F)F)c(CCl)s1
Agent: BrCC1CCCCO1
Product: Nc1nc(C(F)(F)F)c(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)s1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(chloromethyl)-4-(trifluoromethyl)thiazol-2-amine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, 1′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one was obtained (4.0%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, DMSO-d6) δ7.39 (br, 2H), 7.32 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=6.7 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.69 (s, 1H), 6.12 (s, 1H), 5.91 (s, 2H), 5.02 (ABq, 2H), 4.70 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 167.9, 155.9, 148.9, 142.2, 141.8, 134.7 (q, 1JCF=135 Hz), 132.1, 129.5, 124.5, 123.9, 123.8 (m), 119.9, 109.2, 103.2, 101.9, 93.9, 80.2, 57.8, 40.9; MS (ES+) m/z 462.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl.[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][C:24]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:23]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccccc1Cl
Product: O=C(NCc1ccccc1Cl)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 2-Chloro-benzylamine. MS (ESI): 482.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:12]([F:17])[F:16])[C:3]=1[F:10]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1c(Cl)ccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1c(Br)ccc(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-6-chloro-2-fluorophenol (1.00 g, 4.44 mmol) and sodium chlorodifluoroacetate in dimethylformamide (DMF; 9 mL) was added potassium carbonate (1.22 g, 5.32 mmol) and water (1.77 mL) and the resulting mixture heated to 100° C. for 4 hours. The solution was cooled to ambient temperature and concentrated hyrdrochlroric acid (2.5 mL) and water (4 mL) were added and stirred at ambient temperature overnight. The solution was cooled in an ice bath and neutralized with 2N sodium hydroxide and then extracted with ethyl ether (2×25 mL). The combined extracts were washed with brine, dried (sodium sulfate), and concentrated to give 1-bromo-4-chloro-2-fluoro-3-difluoromethoxybenzene (1.20 g, 4.2 mmol). This material was used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[NH:13][CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl.O>C(O)C>[ClH:22].[NH:20]([N:21]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][C:14]2[NH:13][CH:12]=[CH:11][C:10]1=2)[C:17]([NH2:19])=[NH:18]
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]ccc21
Yield: 44.3 %

Procedure:
A mixture of 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.11 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.026 ml), water (0.026 ml) and ethanol (10 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 4N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 1) (70 mg) as colorless crystals.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:11]1)=[O:7])(C)(C)C.[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24].[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:26]([NH:25][CH2:22][CH2:23][CH3:24])=[O:27])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CCCN=C=O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCCN)C1
Product: CCCNC(=O)NCCCCCCN1CC[C@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
6-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)hexylamine (1.50 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.50 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (1.01 g) to give 4-amino-5-chloro-2-methoxy-N-((3R)-1-(6-(3-n-propylureido)hexyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:10][C:9]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:8][C:7]=1[CH3:22]>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[CH:2]([C:6]1[S:10][C:9]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:8][C:7]=1[CH3:22])=[O:1]
Reactant: CC(=O)Nc1nc(C=Cc2cc(C)c(C3OCCO3)s2)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCc2cc(C)c(C=O)s2)cs1
Yield: 58.6 %

Procedure:
N-(4-{2-[5-(1,3-Dioxolan-2-yl)-4-methylthiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (4.42 g, 13.1 mmol) was dissolved in a mixture of ethyl acetate (400 ml) and acetic acid (100 ml), and 10% palladium carbon (2.21 g, containing 50% water) was added. The mixture was hydrogenated at room temperature under an atmospheric pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 200 g, ethyl acetate:dichloromethane=1:6) to give N-{4-[2-(5-formyl-4-methylthiophen-2-yl)ethyl]-1,3-thiazol-2-yl}acetamide (2.26 g, 7.68 mmol, yield 58.4%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[C@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.Br[C:41]1[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([NH:8][C@H:9]1[C@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:41]2[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NCc3ccccc3)C2)nc1C
Yield: 20.9 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-3-(benzylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (203a) (50.0 mg, 0.108 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (32 mg, 0.130 mmol) and sodium carbonate (115 mg, 1.08 mmol), to obtain 12 mg of the title compound (21%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC([CH:24]2[CH2:28][CH2:27]C[O:25]2)=NC=1C.IC1NC(C)=NC=1C>>[CH3:17][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:4]1[NH:3][C:2]([CH:1]2[CH2:27][CH2:28][CH2:24][O:25]2)=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(C2CCCO2)[nH]c1I
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCCO2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-2-yl)-1H-imidazole (compound 173.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21](O)[OH:22])[O:19][CH:20]=2)[CH:14]=1.[CH3:29][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:22])[CH3:29])[O:19][CH:20]=2)[CH:14]=1
Reactant: C[Al](C)C
Reactant: O=C(Nc1cnn(Cc2coc(C(O)O)n2)c1)OCc1ccccc1Cl
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-dihydroxymethyl-oxazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (212 mg, 0.56 mmol) in CH2Cl2 (4.0 mL) was treated at 0° C. with trimethylaluminum (1.40 mL of a 2M solution in toluene, 2.80 mmol). The reaction mixture was then stirred at 0° C. for 1 h and at rt for 16 h. Sat. aq. NH4Cl was then added and the aq. layer was extracted with CH2Cl2 (3×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.28. LC-MS-conditions 02: tR=0.86 min, [M+H]+=377.17.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[C:13]([Br:15])[CH:14]=1.[H][H]>[Ni]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1
Reactant: [H][H]
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Agent: [Ni]
Product: CN1CCC[C@H]1COc1cncc(Br)c1

Procedure:
A sample of 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-bromo-pyridine-N-oxide, from Example 98a above, is reacted with hydrogen in the presence of Raney nickel according to the method of Y. Tamura et al., Heterocycles, 15:871-874 (1981). The solvents are removed, and the product is extracted, then purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[O:28]1[CH2:33][CH2:32][NH:31][C@@H:30]2[CH2:34][CH2:35][CH2:36][C@@H:29]12.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:31]4[CH2:32][CH2:33][O:28][C@@H:29]5[CH2:36][CH2:35][CH2:34][C@@H:30]45)=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C1C[C@H]2NCCO[C@@H]2C1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 90 mg, 0.202 mmol), (4aR,7aR)-octahydrocyclopenta[b][1,4]oxazine (51.5 mg, 0.405 mmol), potassium fluoride (58.8 mg, 1.01 mmol), DMSO (0.62 mL), and N,N-diisopropylethylamine (0.18 mL, 1.01 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-((4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H31ClN6O [M+H]+ 491. found 491.
Reaction SMILES: N[C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2([CH3:20])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH3:19])=[CH:13][C:14]=3[CH3:18])[O:9]2)=[CH:4][CH:3]=1.[ClH:23].N([O-])=O.[Na+].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30]>O.CC(C)=O>[Cl:23][CH:29]([CH2:30][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2([CH3:20])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH3:19])=[CH:13][C:14]=3[CH3:18])[O:9]2)=[CH:4][CH:3]=1)[C:28]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Cl
Reactant: Cc1cc(C)c2c(c1)OC(C)(COc1ccc(N)cc1)CC2
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)cc(C)cc3O2)cc1

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 2.0 g of 2-(4-aminophenoxymethyl)-2,5,7-trimethylchroman (prepared as described in Preparation 26), 2 ml of concentrated aqueous hydrochloric acid, 560 mg of sodium nitrite, 15 ml of acetone, 3.5 ml of ethyl acrylate, 90 mg of cuprous oxide and 2 ml of water were reacted, to afford 1.53 g of the title compound as a pale yellow oil.