Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[N:8][C:7]([O:6][CH2:5][C:4]3[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=3)=[C:12]([CH:11]=2)[C:13]([Cl:43])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid (120 mg, 0.20 mmol) from Example 77 in methylene chloride (3 mL) was added a drop of DMF (cat.) and oxalyl chloride (0.100 mL, 1.1 mmol). The reaction was stirred at rt for 1 h and was then evaporated to dryness. The acid chloride was dissolved in methylene chloride and used directly in the subsequent amide formation.
Reaction SMILES: [CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[OH-:30].[Na+].[CH2:32]([OH:34])[CH3:33]>O1CCCC1>[CH:1]1([N:4]([CH2:7][C:8]2[C:9]([CH:27]([CH3:29])[CH3:28])=[CH:10][CH:11]=[CH:12][C:13]=2[C:28]#[C:27][C:9]2[CH:10]=[CH:11][C:33]([C:32]([OH:30])=[O:34])=[CH:7][CH:8]=2)[CH2:5][CH3:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C(C)C)c2)cc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(Cc1c(C#Cc2ccc(C(=O)O)cc2)cccc1C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg, 15.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (72%) of the title compound as a pale-yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[S:23])=[CH:3][CH:2]=1.Cl[CH2:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:33]1[CH:34]=[CH:35][C:30]([S:29][CH2:28][CH2:27][CH2:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[S:23])=[CH:31][CH:32]=1
Reactant: O=c1c2ccccc2[nH]c(=S)n1CCCCSc1ccncc1
Reactant: ClCCCCSc1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2n(CCCCSc2ccncc2)c(=S)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 515 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2(1H)-thion-4-(3H)-one and 332 mg (1.65 mmol) of 4-(4-chlorobutylthio)pyridine in 15 ml of dimethylformamide, 0.25 ml (1.65 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/ethanol=25:1 to 10:1) to give 0.694 mg of the desired product (97.1% yield; colorless oil).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Reactant: N
Product: Cc1ccccc1COc1cccnc1NC(=N)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-[3-(2-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (0.99 g, 0.0026 mol), yellow mercuric oxide (0.67 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirred at room temperature for 48 hours. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.59 g (62%), m.p. 158°-159 ° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[Ir:10](Cl)(Cl)Cl.[C:14]1([C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Ir+3:10].[C:14]1([C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([C:20]2[S:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8]
Reactant: Cl[Ir](Cl)Cl
Reactant: O=C(O)c1ccccn1
Agent: c1ccc(-c2nc3ccccc3s2)cc1
Solvent: ClCCl
Product: O=C([O-])c1ccccn1
Product: [Ir+3]
Temperature: 25 °C

Procedure:
2.14 mmol (0.26 g) of picolinic acid was added to a room-temperature solution of 0.80 mmol 2-phenylbenzothiazole Iridium chloride dimer (1.0 g) in 60 mL of dichloromethane. The mixture was heated to reflux under nitrogen in an oil bath for 8.5 hours. The reaction mixture was cooled to room temperature, and the yellow precipitate was filtered off via vacuum. The filtrate was concentrated and methanol was added to precipitate more product. Successive filtrations and precipitations yielded about 900 mg of impure product. Emission spectrum is in FIG. 45.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[CH2:23]([NH:22][C:20]1[CH:19]=[CH:18][C:17]([S:30][C:31]2[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(NCc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (105 mg, 0.50 mmol) was reacted with the product from Example 44c (161 mg, 0.50 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (68 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.83 (sext, J=7.35 Hz, 2H) 2.97 (dd, J=7.35 Hz, 2H) 4.29 (m, 2H) 6.15 (d, J=6.99 Hz, 1H) 6.51 (d, J=8.46 Hz, 2H) 6.93 (d, J=8.46 Hz, 2H) 7.22-7.38 (m, 8H) 7.78 (d, J=8.83 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 9.66 (s, 1H) 10.90 (br s, 1H) 14.21 (br s , 1H); MS (ESI+) m/z 493 (M+H−TFA)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH:22]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:26]([CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:28])=[O:27])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CCC2)c2n(c1=O)CCO2
Yield: 5.1 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 400 mg, 0.99 mmol) in pyridine (4 ml) was reacted with cyclobutanesulfonyl chloride (274 mg, 1.7 mmol) to afford the crude product. Purification by preparative HPLC afforded 26 mg of the product (5% yield).
Reaction SMILES: C(NCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:33]([C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1)=O.[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46].[BH3-]C#N.[Na+]>>[CH3:43][C:44]([CH3:48])([CH3:47])[CH2:45][NH:46][CH2:33][C:35]1[S:39][C:38]([B:40]([OH:42])[OH:41])=[CH:37][CH:36]=1
Reactant: CC(C)(C)CN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)CNCc1ccc(B(O)O)s1
Yield: 100.4 %

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (2,2-dimethylpropyl)amine (0.037 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 21 mg of the title compound (21%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([N:15]=[N+:16]=[N-:17])[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@H:12]([OH:11])[C@@H:10]([N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](N=[N+]=[N-])C1

Procedure:
To a stirring solution of (±)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (2.4 g, 12.06 mmol) in ethanol (20 mL) was added sodium azide (1.00 g, 15.62 mmol) and ammonium chloride (840 mg, 15.79 mmol). The resulting mixture was heated to reflux overnight and then partitioned between ethyl acetate and water. The combined organic layers were washed with brine, separated and dried (MgSO4). The crude product was purified by column chromatography to yield (3R*,4R*)-4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.95 g) and (3S*,4S*)-3-azido-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (312 mg).
Reaction SMILES: C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[C:26]([O:30][C:31](=[O:42])[NH:32][CH2:33][C:34]1[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][C:35]=1[Br:41])([CH3:29])([CH3:28])[CH3:27].[F:43][C:44]1[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH3:55])=[CH:48][C:45]=1[CH:46]=O.C[Si]([C:60]#[N:61])(C)C>ClCCl>[C:26]([O:30][C:31](=[O:42])[NH:32][CH2:33][C:34]1[CH:39]=[C:38]([NH:40][CH:46]([C:60]#[N:61])[C:45]2[CH:48]=[C:49]([O:54][CH3:55])[C:50]([O:52][CH3:53])=[CH:51][C:44]=2[F:43])[CH:37]=[CH:36][C:35]=1[Br:41])([CH3:29])([CH3:27])[CH3:28]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1Br
Reactant: COc1cc(F)c(C=O)cc1OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: COc1cc(F)c(C(C#N)Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Yb(OTf)3(0.399 g) and dichloromethane (25 mL) there were added (5-amino-2-bromobenzyl)carbamic acid t-butyl ester (Example (3a))(1.95 g), 2-fluoro-4,5-dimethoxybenzaldehyde (1.19 g), MS3A (2.58 g) and trimethylsilyl cyanide (1.29 mL) in that order under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The solvent in the mixture was distilled off under reduced pressure, ethyl acetate (200 mL) and water (100 mL) were added to the residue, and after sufficiently shaking the mixture, the organic layer was separated off, washed with saturated aqueous sodium chloride (100 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (2.98 g) as a colorless solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].C(CS[C:12](=[S:18])SCC(O)=O)(O)=O.[C:19]([NH:27][NH:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C(O)C>[C:19]([NH:27][NH:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:12]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([NH:28][NH:27][C:1](=[O:4])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:34][CH:33]=2)=[S:18])=[CH:33][CH:34]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(NNC(=O)c2ccccc2)cc1
Reactant: O=C(O)CSC(=S)SCC(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NNc1ccc(NC(=S)Nc2ccc(NNC(=O)c3ccccc3)cc2)cc1)c1ccccc1

Procedure:
Sodium carbonate (4.65 g, 0.044 mole) was dissolved in a solvent mixture of water (95 ml) and ethanol (30 ml). Bis(carboxymethyl)trithiocarbonate (2.5 g, 0.011 mole) was added portionwise. Vigorous stirring of the reaction mixture was maintained until all solid was dissolved. It was then heated to 80°-85° C and 1-benzoyl-2-(4-aminophenyl)hydrazine (5.0 g, 0.022 mole) was added in one portion. Stirring and heating were maintained for one and one-half hour and the reaction mixture was then chilled. The solid was removed by filtration, washed and dried. Yield 2.05 g (37%), m.p. 185°-187° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:8][C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][C:13]([Cl:20])=[CH:14][CH:15]=2)[N:10]=1.CCN(C(C)C)C(C)C.C1COCC1>CCOC(C)=O>[Cl:8][C:9]1[N:18]=[C:17]([O:19][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]2[C:11](=[CH:12][C:13]([Cl:20])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=c1[nH]c(Cl)nc2cc(Cl)ccc12
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCOc1nc(Cl)nc2cc(Cl)ccc12
Reaction time: 16 h
Yield: 84.6 %

Procedure:
2-methoxyethoxymethyl chloride (1.0 mL, 8.8 mmol) was added dropwise to a solution of 2,7-dichloro-4-oxoquinazoline (1.7 g, 7.8 mmol), DIEA (2.1 mL, 12 mmol), and THF (20 mL). The reaction was allowed to proceed at rt for 16 h, and then EtOAc was added (250 mL). The solution was washed with water (2×100 mL) and brine (100 mL). The organic layer was then dried and concentrated, and the resulting residue was triturated with EtOH to provide the titled compound (2.0 g, 83%). This material was used directly without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]#[C:10][NH2:11].[CH2:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[Br:1][CH2:12][CH:13]([NH:9][C:10]#[N:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CN
Reactant: C=Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#CNC(CBr)c1ccccc1
Reaction time: 0.08 h
Yield: 79.8 %

Procedure:
N-bromosuccinimide (10.68 g, 0.06 mol) and cyanamide (4.2 g, 0.1 mol) were dissolved in 150 m of dichloromethane and the mixture was stirred for 5 min. To this mixture was added a solution of styrene (5.2 g, 0.05 mol) in 20 m of dichloromethane using a dropping funnel for one hour. The resulting reaction mixture was stirred at room temperature for 12 hours, washed with an equal volume of 5% sodium thiosulfate and brine which were freshly prepared, dried over anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography (eluent:ethylacetate/toluene=1/20, v/v) to afford 8.98 g of 2-bromo-1-phenylethyl cyanamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH3:17][N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([CH:11]1[CH2:10][CH2:9][C:8](=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: CNc1ccccc1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C1CCC(=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Oxalyl chloride (0.89 g, 7.0 mmol) and a few drops of dry DMF are added to a stirred solution of 4-oxo-cyclohexanecarboxylic acid (0.50 g, 3.5 mmol) in CH2Cl2 (7 ml) and the reaction is kept stirring at rt overnight. The volatiles are removed under reduced pressure, the residue is azeotroped with toluene and dried under high vacuum yielding crude acid chloride. This material is reacted without further purification with N-methylaniline (0.16 g, 1.5 mmol) in CH2Cl2 (7 ml) in the presence of DIEA (0.58 g, 4.5 mmol). After stirring overnight at rt, saturated aqueous NaHCO3 is added and the mixture extracted three times with CH2Cl2. The combined organic layers are dried over Na2SO4 and evaporated. The residue is column chromatographed on silica gel (hexane/EtOAc 2:1) and the title compound is obtained as a pale yellow solid (0.47 g) in 57% yield. tR (LC-4) 0.89 min; ESI-MS (positive ion): m/z 231.98 [M]+ (calcd 231.13 for C14H17NO2).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.N1C=CC=C(CN)C=1.[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:9][CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[CH:2][CH:3]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Reactant: NCc1cncc(F)c1
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1cccnc1
Yield: 40 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-3-ylmethanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 40% yield: 1H NMR (300 MHz, CDCl3) δ 8.58-8.52 (m, 2H), 7.69-7.66 (m, 1H), 7.28-7.23 (m, 1H), 6.20-6.17 (m, 1H), 4.57 (d, J=5.8 Hz, 2H), 4.12-4.07 (m, 2H), 3.61-3.55 (m, 2H), 3.10 (d, J=7.4 Hz, 2H), 2.61 (s, 3H), 1.96-1.87 (m, 1H), 0.92 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.4, 155.6, 153.5, 149.1, 148.7, 135.5, 133.9, 123.5, 116.6, 51.5, 42.8, 41.9, 41.2, 26.7, 19.9, 17.2; MS (ES+) m/z 373.9 (M+1).
Reaction SMILES: [OH-].[K+].C(OC(C)C)(C)C.[CH:10]#[C:11][CH:12]([OH:14])[CH3:13].[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1=[O:25])[CH3:16]>O>[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1=[O:25])[CH3:16].[CH2:15]([CH:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]1([OH:25])[C:10]#[C:11][CH:12]([OH:14])[CH3:13])[CH3:16]
Reactant: C#CC(C)O
Agent: CCC1CCCC(C)(C)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCC1CCCC(C)(C)C1(O)C#CC(C)O
Yield: 139.5 %

Procedure:
448 g(8 mole) of KOH and 1100 ml of di-isopropyl-ether were first introduced into a reaction vessel fitted with cooling and stirring devices. 154 g (2.2 mole) of but-1-yn-3-ol were then added to the above mixture (temperature 25°-30°; addition period: 30 min), followed by 308 g (2.0 mole) of 2-ethyl-6,6-dimethyl-cyclohexanone (addition period: 30 min; dropwise). The reaction mixture was then stirred at 35° for 17 hours and, after cooling, 500 ml of water were progressively added thereto. After separation of the organic phase, washing with 5% aqueous H2SO4 (200 ml), drying over Na2SO4, concentration and final distillation, there were isolated a first portion of unreacted 2ethyl-6,6-dimethyl-cyclohexanone (46 ) and 313 g(78% yield) of 2-ethyl-6,6-dimethyl-1-hydroxy-1-(3-hydroxy-but-1-yn-1-yl)-cyclohexane.
Reaction SMILES: [NH2:1][C:2](=[O:25])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[O:11][CH:10]([C:16]([F:19])([F:18])[F:17])[C:9]([C:20]([O:22]CC)=[O:21])=[CH:8]2.O.[OH-].[Li+].C(O)C>C1COCC1.O>[NH2:1][C:2](=[O:25])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[O:11][CH:10]([C:16]([F:17])([F:18])[F:19])[C:9]([C:20]([OH:22])=[O:21])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(/C=C/C(N)=O)cc(Cl)c2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)/C=C/c1cc(Cl)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 80 °C
Yield: 48.6 %

Procedure:
The product of step 1 was dissolved in 3 mL of THF and treated with a solution of 0.13 g (2.55 mmol) lithium hydroxide hydrate in 3 mL of water. The mixture was treated with 3 mL of ethanol and heated to 80° C. for two hrs. The volatiles were removed, the residue was acidified at 0° C. to pH=1.0 with dilute hydrochloric acid. The product was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Concentration of the organic fraction afforded 0.169 g (48.6%) of an off-white solid: 1H NMR(DMSO/300 MHz) 7.87(s, 1H), 7.70(d, J=2.1 HZ, 1H), 7.55(d, J=2.1 Hz, 1H), 7.48(d, J=15.9 Hz, 1H), 6.63(d, J=15.9, 1H), 5.96(q, J=6.6 Hz, 1H). MS (ESI+) 348.0 (M+1, 100). MS(ES−) 346.0(M−1, 100). HRMS (ES−) m/z calcd for (M−H; C14H8ClF3NO4): 346.0088, found 346.0078.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4]1.[S:23]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:56]>CO.CO.C(Cl)Cl>[ClH:56].[ClH:56].[S:23]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH2:2][C@@H:3]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[CH:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCS2
Reactant: NC[C@@H]1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)C1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CC[C@@H](CNCc2cc3c(cn2)OCS3)C1
Reaction time: 8 h

Procedure:
To a 10 mL round-bottomed flask were added (1R)-1-{[(3S)-3-(aminomethyl)-1-pyrrolidinyl]methyl}-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (60 mg, 0.200 mmol), [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (33.4 mg, 0.200 mmol) (for a synthesis see WO2004058144 Example 61), and sodium sulfate (250 mg, 1.760 mmol) in DCM (4 ml) and methanol (1.00 ml) to give an orange suspension. The reaction was stirred overnight under nitrogen. Sodium triacetoxyborohydride (85 mg, 0.400 mmol) was added and the reaction was stirred for 3 h. The reaction mixture was diluted with 10% MeOH/DCM (20 mL), filtered, adsorbed onto silica and then purified by silica chromatography eluting with 0-10% MeOH/DCM (1% NH4OH) to give the free base of the title compound as a yellow oil. LCMS/NMR consistent with the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCC1
Reactant: N#CCc1ccsc1
Product: N#CC(=C1CCCC1)c1ccsc1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and cyclopentanone.