Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/C)\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].C(O)(=[O:16])C#CC.[Li]N1C(C)(C)CCCC1(C)C.BrCC=C(C)C>>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([OH:1])=[O:16]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: CC#CC(=O)O
Agent: CC(C)=CCBr
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: CC(C)=CCCC#CC(=O)O

Procedure:
The overall process can be illustrated by the manufacture of nerol, ((Z)-3,7-dimethylocta-2,6-dien-1-ol), which begins with the treatment of 2-butynoic acid with lithium 2,2,6,6-tetramethylpiperidide, followed by alkylation with 1-bromo-3-methyl-2-butene to yield 7-methyloct-6-en-2-ynoic acid as the major product. 2-Ethenylidene-5-methyl-4-hexenoic acid is produced as a minor product in the course of the alkylation. The acids are esterified conveniently with methyl iodide, and treated with morpholine, followed by acid workup, to give a mixture of a major amount of methyl 7-methyloct-6-en-2-ynoate and a minor amount of methyl 2-acetyl-5-methyl-4-hexenoate. The latter compounds are separated by chromatography on a silica gel column using ethyl acetate-n-hexane as eluant. Contacting of the isolated methyl 7-methyloct-6-en-2-ynoate with a mixture of lithium dimethyl cuprate and methyl copper at low temperatures gives methyl (Z)-3,7-dimethylocta-2,6-dienoate, which is reduced to nerol, (Z)-3,7-dimethylocta-2,6-dien-1-ol, for example, with aluminium hydride.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:11]([CH3:13])[CH3:12])[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[N:6]=1)=O.[NH3:30]>CO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[N:7]1[C:8]([CH2:10][N:11]([CH3:12])[CH3:13])=[N:9][C:5]([C:3]([NH2:30])=[O:2])=[N:6]1)=[O:29]
Reactant: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: N
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8.66 g (0.020 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester is covered over with 400 ml of methanol and 80 ml of concentrated aqueous ammonia solution. The reaction solution is stirred for 16 hours at room temperature, and thereupon concentrated in vacuo to dryness. Water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed twice with ice-cold 1N sodium hydroxide solution and is then extracted twice with 2N hydrochloric acid solution. To the aqueous acidified solutions there are added ice and sufficient 5N sodium hydroxide solution to bring the pH-value to 10. The precipitated base is taken up in methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated by evaporation to dryness. The amorphous residue is triturated with ether, whereupon the reaction product precipitates in crystalline form. It is filtered off with suction and washed with ether. After drying, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide, m.p. 177°-180°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([CH2:33]O)[CH:27]=2)([CH3:22])[CH3:21].C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][CH2:33][C:28]1[CH:27]=[C:26]2[C:30](=[CH:31][CH:32]=[C:23]([CH:20]([CH3:22])[CH3:21])[CH:24]=[CH:25]2)[CH:29]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)c1ccc2cc(CO)cc-2cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)c1ccc2cc(CCl)cc-2cc1

Procedure:
Triphenylphosphine (0.66 g) was added to a solution of (6-isopropylazulen-2-yl)methanol (0.5 g) in carbon tetrachloride (10.0 ml) and the mixture was refluxed with heating for 15 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (n-hexane-diethyl ether) to obtain 2-(chloromethyl)-6-isopropylazulene (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(Cl)c(=O)[nH]1
Product: CSc1ncc(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 86 %

Procedure:
A suspension of 5-chloro-2-(methylthio)pyrimidin-4(3H)-one (24 g, 0.136 mol) in POCl3 (200 mL) was heated at reflux for 2 hrs. The reaction mixture was then cooled to room temperature and was concentrated to remove excessive of POCl3. The residue was then treated with H2O (150 mL) and was adjusted to pH=7˜8 with aq. K2CO3. The resulting mixture was extracted with CH2Cl2 (50 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and dried on vacuum to give title compound (23 g, 86%) as a light brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[O:12]=[C:13]1[CH2:17][O:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].N1CCCCC1>C(O)C>[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([CH:10]=[C:17]2[O:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]2=[O:12])=[CH:2]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of 7-azaindole-3-carboxaldehyde (0.10 g, 0.70 mmol) and ethyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.70 mmol) in ethanol (3.0 mL), piperidine (0.083 mL, 0.84 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with cold ethanol and isopropyl ether then dried to afford the titled compound (0.13 g, y. 48%).
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20]([CH3:27])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:30]=[C:31]1[O:35][CH:34]([O:36][CH2:37][CH2:38]C2C=CC=CC=2)[CH:33]([NH:45][C:46](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:47])[CH2:32]1>>[CH2:37]([O:36][CH:34]1[CH:33]([NH:45][C:46]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:29])[CH:14]([NH:16][C:17](=[O:28])[C:18]2[CH:19]=[C:20]([CH3:27])[C:21]([O:25][CH3:26])=[C:22]([CH3:24])[CH:23]=2)[CH3:15])=[O:47])[CH2:32][C:31](=[O:30])[O:35]1)[CH3:38]
Reactant: COc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1cc(C)c(OC)c(C)c1
Yield: 81 %

Procedure:
Prepared from 1-[2-(4-methoxy-3,5-dimethyl-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 174 mg (81% yield) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 1.04 (t, 0.45H), 1.27 (t, 2.55H), 1.34-1.45 (m, 3H), 1.95-2.45 (m, 10H), 2.78-2.84 (m, H), 3.60-3.90 (m, 8H), 4.50-4.70 (m, 2H), 4.90-4.94 (m, H), 5.45 (d, 0.85H), 5.61 (d, 0.15H), 6.99 (d, H), 7.15 (d, H), 7.45 (s, 2H); retention time on analytical HPLC: 10.09 min; LC-MS: m/z=476 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:30])[N:12]([CH3:29])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:30])[N:12]([CH3:29])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a solution of 3-hydroxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (428.2 mg, 1.01 mmol) (obtained as described in Reference Example 58(4)) in methylene chloride (21.4 ml) were added methanesulfonyl chloride (0.25 ml, 3.23 mmol) and triethylamine (0.45 ml, 3.23 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (15:1) as the eluant to afford 3-methanesulfonyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (480.1 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC[C:16](OCC)=[O:17].CC[O-].[Na+].COC1C=CC(S)=CC=1>>[CH3:16][O:17][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CSc1ccccc1
Agent: CC[O-]
Agent: COc1ccc(S)cc1
Agent: [Na+]
Product: CCOC(=O)CSc1ccc(OC)cc1

Procedure:
The procedure is as in Example 2 for the preparation of ethyl (phenylthio)acetate starting with ethyl bromoacetate (11.7 g), a 2M ethanolic solution of sodium ethylate (35 cc) and 4-methoxythiophenol (10 g). Ethyl (4-methoxyphenylthio)acetate (13.6 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:28]1[C:27]([S:26][C:25]2[N:16]([CH2:15][CH2:14][CH2:13][NH:12][CH:10]([CH3:11])[CH3:9])[C:17]3[C:18]([N:24]=2)=[C:19]([NH2:23])[N:20]=[CH:21][N:22]=3)=[CH:32][C:31]2[O:33][CH2:34][O:35][C:30]=2[CH:29]=1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccco2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C

Procedure:
2-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 12.5:1) to give 19.1 mg (72%) of DZ3-4. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.18 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.25 (s, 1H), 6.96 (s, 1H), 6.71 (d, J=3.3 Hz, 1H), 6.47 (dd, J=1.8, 3.2 Hz, 1H), 6.06 (s, 2H), 4.20 (t, J=7.0 Hz, 2H), 2.87 (m, 1H), 2.61 (t, J=6.9 Hz, 2H), 2.00 (m, 2H), 1.14 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.3, 152.2, 151.2, 150.9, 149.5, 148.14, 148.08, 142.4, 129.0, 119.2, 117.5, 114.5, 111.5, 110.0, 109.0, 102.3, 42.8, 41.0, 28.5, 21.2; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O3S, 453.1709; found. 453.1705; HPLC: method A Rt=6.23, method B Rt=6.82.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[N:37]=[C:38]=[O:39]>O1CCCC1>[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]=1[NH:37][C:38]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:39]
Reactant: Cc1onc(-c2ccccc2)c1N=C=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 5-methyl-3-phenyl-4-isoxazolyl isocyanate (244 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 229 mg (63.3%) of the desired product as a solid.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1C=C[C:24]2C(CCO)=[CH:26][O:27][C:23]=2[CH:22]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:26][O:27][C:23]1[CH:24]=[CH:2][C:3]2[C:4]([CH2:1][CH2:5][O:6][C:7]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:8]=3[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]4)=[CH:19][O:20][C:21]=2[CH:22]=1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: COc1ccc2c(CCO)coc2c1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccc2c(CCOc3cccc4[nH]c(C(=O)O)cc34)coc2c1

Procedure:
4-[2-(6-methoxy-benzofuran-3-yl)-ethoxy]-1H-indole-2-carboxylic acid (16o) is synthesized analogous to 16a from 4-[2-(6-methoxy-benzofuran-3-yl)-ethanol 21 (synthesis see below) and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[OH:36][C:37]([CH3:42])([CH3:41])[C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:38](=[O:39])[C:37]([OH:36])([CH3:42])[CH3:41])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)C(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
To 1-(2-chloro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1 of Example 312, were added 2-hydroxyisobutyric acid (7.0 mg, 0.07 mmol), dichloromethane (1.0 mL), HOBT (15.0 mg, 0.11 mmol), EDAC (21.0 mg, 0.11 mmol), and triethylamine (23.0 uL, 0.17 mmol). The reaction mixture was stirred at room temperature for 12 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Br:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:33]=[CH:32][C:24]2[N:25]([CH3:31])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[CH:22]=1.Cl>C(O)CCC.O1CCOCC1>[Br:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:33]=[CH:32][C:24]3[N:25]([CH3:31])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Br
Yield: 48.4 %

Procedure:
2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide (52 mg, 0.15 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (29 mg, 0.15 mmol) were combined in 5 mL n-butanol. A drop of a solution of 4N hydrochloric acid in dioxane was added and the mixture was refluxed for five hours. The mixture was concentrated and triturated with ether. The remaining solid was partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated, was dried (sodium sulfate), and was concentrated to afford an oil which was purified on silica (methanol:dichloromethane gradient elution) to afford 36 mg (48%) of 2-[5-bromo-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an off-white solid. Mp: 238-40° C.; MS: 496.61 (M+H); 1H NMR (chloroform-d): δ 10.95 (s, 1H), δ 8.58 (d, J=8 Hz, 1H), δ 8.22 (s, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.44 (m, 3H), δ 7.11 (t, J=8 Hz, 1H), δ 7.01 (s, 1H), δ 6.25 (br s, 1H), δ 3.35 (s, 3H), δ 3.06 (s, 3H), δ 2.67 (m, 2H), δ 2.33 (t, J=7 Hz, 2H), δ 2.16 (m, 2H).
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[C:17]([CH3:24])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:25]([C:27]1[C:32]2[N:33]([CH2:36][C:37](O)=[O:38])[CH:34]=[N:35][C:31]=2[CH:30]=[CH:29][CH:28]=1)#[N:26].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>O>[C:11]([C:15]1[N:20]=[CH:19][C:18]([CH:21]([NH:23][C:37](=[O:38])[CH2:36][N:33]2[C:32]3[C:27]([C:25]#[N:26])=[CH:28][CH:29]=[CH:30][C:31]=3[N:35]=[CH:34]2)[CH3:22])=[C:17]([CH3:24])[CH:16]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: Cc1cc(C(C)(C)C)ncc1C(C)N
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(C)(C)C)ncc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-4-methylpyridin-3-yl)ethyl]amine (intermediate 28) (52 mg, 0.27 mmol), 7-cyanobenzimidazole-1-acetic acid (54.4 mg, 0.27 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (117 μL, 2.5 mmol). Water is added and the reaction is concentrated then purified by reverse phase chromatography. (Yield 31.3 mg, 31%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.27 (s, 9 H), 1.42 (d, J=7.03 Hz, 3 H), 2.29 (s, 3 H), 5.03-5.12 (m, 1 H), 5.13-5.27 (m, 2 H), 7.17 (s, 1 H), 7.34 (dd, J=8.11, 7.71 Hz, 1 H), 7.71 (dd, J=7.62, 0.78 Hz, 1 H), 8.01 (dd, J=8.01, 0.98 Hz, 1 H), 8.34 (s, 1 H), 8.47 (s, 1 H), 8.88 (d, J=7.81 Hz, 1 H). MS [MH+] calc. 376.2137 found 376.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21]C(OCC3C=CC=CC=3)=O)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4].C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH2:21])[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:32][CH3:33])=[O:4]
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Yield: 90.9 %

Procedure:
cis-4-Benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (322 mg, 0.71 mmol), 10% palladium on carbon (32 mg) and cyclohexene (9 ml) in 16 ml ethanol was heated to 80° C. for 1.25 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using 1% isopropanol-dichloromethane afforded the title product (208 mg, 91%). 1H NMR (DMSO-d6) δ 1.02 (d, 3H), 6.68 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Yield: 105.6 %

Procedure:
4-Bromo-3-methylaniline (7.40 g, 40 mmol) and 4-carboxybenzeneboronic acid (7.90 g, 48 mmol) were stirred in 1,2-dimethyoxyethane (DME) (150 ml). Anhydrous sodium carbonate (19.0 g, 179 mmol) was dissolved in water (150 ml) and added to the above. The mixture was then purged with a stream of argon for 15 minutes. Tetrakis (triphenylphosphine)palladium (O) (0.25 g, 0.2 mmol) was added, and the mixture was stirred at reflux for 20 h under argon. DME was removed by evaporation under reduced pressure, and the clear residue was acidified with 5M HCl to yield a thick grey suspension. The solid was filtered off, washed with water and dried in vacuo at 60° C., to give the title compound (9.60 g, quantitative).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)S[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3N=2)C=CC=CC=1>>[C:14]1([NH:13][C:12]2[CH:7]=[CH:8][C:9]([NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:24]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1

Procedure:
phenothiazine, 2-phenyl-benzimidazole
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1([CH3:21])[CH2:20][CH2:19][CH2:18][NH:17]1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:17]2[CH2:18][CH2:19][CH2:20][C:16]2([CH2:15][O:14][C:13]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH3:21])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OCC2(C)CCCN2)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(OCC2(C)CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
A mixture of methyl 3-nitro4-(2-methyl-2-pyrrolidinylmethoxy)benzoate (0.188 g, 0.920 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (0.289 g, 0.920 mmol), HOBt (0.149 g, 1.10 mmol), DMAP. (11.2 mg, 0.0920 mmol) and EDC (0.211 g, 1.10 mmol) in DMF (5 mL) was stirred for 14 hr at room temp. EtOAC was added to the mixture and the solution was washed successively with 0.5 N HCl, sat. NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to afford 0.489 g (q.y.) methyl 4-[[1-[3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-methyl-2-pyrrolidinyl]methoxy]-3-nitrobenzoate as a yellow crystalline material. 1H-NMR (CDCl3) δ 1.26 (d, J=5.9 Hz), 1.85–4.50 (m, 10H), 2.30 (s, 3H), 3.67 (s, 2H), 3.92 (s, 3H), 6.36 (s, 2H), 6.75–7.52 (m, 7H), 8.02 (d, J=7.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.47 (s, 1H).