Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][C@H:33]([CH:36]([CH3:38])[CH3:37])[C:34]#[N:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([C@H:33]([NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH:36]([CH3:38])[CH3:37])#[N:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)[C@@H](N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 39.8 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 40 mg, 0.093 mmol), (R)-2-amino-3-methylbutanenitrile (Int-VII, 9.10 mg, 0.093 mmol), HATU (45.8 mg, 0.121 mmol), and 4-methylmorpholine (37.5 mg, 0.371 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 35 min, 20 mL/min, 220 nM, product retention=30.3 min) to provide single enantiomer N—((R)-1-cyano-2-methylpropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.037 mmol, 40.1% yield): LCMS=512.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, d, J=8.58 Hz), 8.13-8.26 (2 H, m), 7.50-7.81 (7 H, m), 5.21 (1 H, s), 4.54-4.69 (1 H, m), 2.05-2.25 (1 H, m), 1.09 (3 H, d, J=6.82 Hz), 0.98 (3 H, d, J=6.60 Hz); HPLC peak RT=10.5 min (Method A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24]C)=[O:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Agent: Cl
Product: O=C(O)C1CCN(S(=O)(=O)c2ccc(-c3ccccn3)cc2)CC1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A stirred solution of methyl 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidine-4-carboxylate (0.25 g, 0.69 mmol) in 5M aqueous HCl (2.5 mL) is heated at 80° C. for 18 h. The mixture is cooled to room temperature resulting in formation of a precipitate. The precipitate is filtered, washed sequentially with 5M aqueous HCl and MeCN and dried in air to give 0.10 g (44%) of 1-{[4-(pyridin-2-yl)phenyl]sulfonyl}piperidine-4-carboxylic acid. m/z=347 [M++H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[N:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccc1F
Yield: 49.6 %

Procedure:
In the same manner as in Reference Example 33 and using tert-butyl (2-fluoro-5-hydroxyphenyl)carbamate (22.4 g, 98.4 mmol), 5-bromo-2-nitropyridine (16.7 g, 82.0 mmol), cesium carbonate (40.1 g, 123 mmol) and N,N-dimethylformamide (140 mL) as starting materials, the title compound (14.2 g, 50%) was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:38]2[CH:39]=[CH:40][C:35]([CH:33]=[O:34])=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4ccc(C=O)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.120 g, 0.217 mmol), 4-formylphenylboronic acid (0.247 mmol) and the procedure described in General Procedure A. 1H NMR (DMSO-d6, 400 MHz) δ 10.12 (s, 1H), 9.53 (s, 1H), 8.03 (s, 1H), 7.97 (d, 1H), 7.78 (t, 1H), 7.71 (d, 1H), 7.64 (m, 2H), 7.62 (s, 1H), 7.55 (m, 3H), 7.36 (s, 1H), 7.24 (m, 1H), 7.16 (d, 1H), 7.12 (d, 1H), 5.72 (br, 2H), 4.05 (s, 3H), 3.93 (s, 3H); MS: (M−H)− 531.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:17]2[N:16]3[C@H:18]([CH3:23])[CH2:19][NH:20][C:21](=O)[C:15]3=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:8]>O1CCCC1>[CH2:7]([C:9]1[C:17]2[N:16]3[C@H:18]([CH3:23])[CH2:19][NH:20][CH2:21][C:15]3=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1cccc2cc3n(c12)[C@H](C)CNC3=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2cc3n(c12)[C@H](C)CNC3
Yield: 100 %

Procedure:
Lithium aluminium hydride (532 mg) was added in portions to a solution of (R)-6-ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (800 mg, 3.50 mmol) in tetrahydrofuran (30 mL) and the resulting suspension was heated to reflux for 1 h. After cooling the reaction was quenched by careful addition of 1 M aqueous sodium potassium tartrate solution (50 mL). Then methanol (50 mL) and ethyl acetate (50 mL) were added, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated to yield the title compound (750 mg, 100%). White solid. ISP-MS: m/e=215.3 ([M+H]t).
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[Na].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1CBr.[OH-].[K+]>O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[CH:24][CH:25]=[CH:26][C:27]=1[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1ccccc1-c1ccccn1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1ccccn1)C(=O)O
Temperature: 130 °C

Procedure:
148 g (0.85 mol) of diethyl methylmalonate were added dropwise at room temperature to 19.5 g (0.85 mol) of sodium in 400 cm3 of H2 O-free EtOH. Subsequently, 211 g (0.85 mol) of 2-(2-pyridyl)benzyl bromide were added dropwise and the mixture was heated under reflux for 3 hours. At room temperature, 143 g (2.55 mol) of KOH dissolved in 500 cm3 of H2O were added and the mixture was heated under reflux for a further 4 hours. The EtOH was distilled off and the residue was admixed with H2O until completely dissolved and subsequently acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated for 1 hour at 130° C. This gave 193 g (94%) of 2-(2-(2-pryridyl)benzyl)propionic acid as solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([O:17]C)=[O:16])=[N:6][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1.[ClH:20]>>[ClH:20].[CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([OH:17])=[O:16])=[N:6][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2cccnc2)cc(OC)c1=O
Agent: Cl
Product: COc1cn(-c2cccnc2)nc(C(=O)O)c1=O
Yield: 95 %

Procedure:
A solution of methyl 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylate (2.0 g, 7.7 mmol) in 6 M HCl aqueous solution (20 ml) was refluxed for 4 h. The mixture was concentrated under reduced pressure to give the title compound (2.1 g, 95% yield) as off-white crystals: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.98 (3H,$), 7.78 (1H, dd, J=8.7, 4.5 Hz), 8.36-8.42 (1H, m), 8.79 (1H, dd, J=4.5, 1.1 Hz), 9.02 (1H, s), 9.15 (1H, d, J=2.6 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:20])[CH2:4][CH2:3]1.[O:21]1[C:30]2[CH:29]=[C:28]([CH:31]=O)[N:27]=[CH:26][C:25]=2[O:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>>[O:21]1[C:30]2[CH:29]=[C:28]([CH2:31][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=5[O:13][CH2:12][C:11]4=[O:20])[CH2:4][CH2:3]3)[N:27]=[CH:26][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: NC1CCN(CCN2C(=O)COc3ccccc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccccc2N1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one (Intermediate 97), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described for Example 21 to give the product as a off-white solid, 81 mg (16%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][N:20]3[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:21]3)=[CH:37][CH:38]=2)[N:4]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyloxazole (312 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (687 mg, yield: 87%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (5:6, volume ratio).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[C:19]([O-])=[O:20]>C(#N)C>[O:20]=[C:19]1[C:9]2[C:8](=[CH:18][CH:17]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:7]=[C:2]2[S:3][CH:4]=[CH:5][N:6]12
Reactant: Clc1nccs1
Reactant: CCOC(=O)c1ccc(N)c(C(=O)[O-])c1
Solvent: CC#N
Product: CCOC(=O)c1ccc2nc3sccn3c(=O)c2c1
Temperature: 150 °C

Procedure:
A mixture consisting of 2.4 gm of 2-chloro-thiazole and 5.6 gm of ethyl 4-amino-isophthalate was heated for eight hours at 150° C on an oil bath. Thereafter, the resulting dark brown oil was refluxed with 10 ml of acetonitrile for one hour, the reaction mixture was then thoroughly cooled, and the crystals formed thereby were collected by suction filtration and recrystallized from a little methanol. The compound of the formula ##STR9##
Reaction SMILES: [C:1]1([C@@H:7]([NH2:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O-])(O)=[O:12].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:10]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9])=[C:11]=[O:12]
Reactant: CC[C@H](N)c1ccccc1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](N=C=O)c1ccccc1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of (S)-1-phenylpropan-1-amine (3.00 g, 14 mmol) in the mixture of methylene chloride (50 mL) and saturated NaHCO3 (50 mL) was added triphosgene (1.40 g, 4.60 mmol) at 0° C. The mixture was stirred for 15 minutes. The organic phase was separated, dried and concentrated to give (5)-(1-isocyanatopropyl)benzene (3.0 g, 88%). 1H NMR (CDCl3): δ=0.93 (q, 3H), 1.81 (m, 2H), 4.50 (m, 1H), 7.13 (m, 2H), 7.22 (m, 1H), 7.50 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:39])[C:20]([C:22]1[C:23]([O:37][CH3:38])=[C:24]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].[H-].[Na+].I[CH3:43]>CN(C)C=O.CO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:39])[C:20]([C:22]1[C:23]([O:37][CH3:38])=[C:24]([N:28]([CH3:43])[C:29]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: CI
Reactant: COc1c(NC(=O)c2ccncc2)cccc1C(=O)N(C)c1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Reaction time: 0.17 h

Procedure:
To the colorless solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-methyl-carbamoyl]-2-methoxy-phenyl]pyridine-4-carboxamide (example G-16 above) (0.120 g, 0.175 mmole) in N,N-dimethylformamide (5 ml), magnetically stirred under argon atmosphere was added sodium hydride (60% suspension in oil) (0.008 g, 0.192 mmole). After the gas evolution stopped, the resulting yellow solution was treated with iodomethane (0.012 ml, 0.027 g, 0.192 mmole). After 10 minutes, two drops of methanol was added and the reaction mixture was evaporated under reduced pressure. The residue was taken up in dichloromethane (5 ml) and water (10 ml). After phase separation, the aqueous solution was extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate and evaporated. The residue was purified on a silica gel column using a gradient of ethyl acetate 20%-cyclohexane 80% to ethyl acetate 60%-cyclohexane 40%. The title product was a pale yellow oil showing, by LC-MS analysis (method 6 described hereunder) a retention time of 1.09 min and a M+H+ mass peak of 700.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:14]2[C:9](=[C:10]([Cl:16])[CH:11]=[CH:12][C:13]=2[Cl:15])[C:7](=[O:8])[O:6]1)#[N:4].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1>>[C:3]([C:5]1([C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[C:14]2[C:9](=[C:10]([Cl:16])[CH:11]=[CH:12][C:13]=2[Cl:15])[C:7](=[O:8])[O:6]1)#[N:4]
Reactant: N#CC1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)ccc(Cl)c32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
21.5 g of NaH in oil dispersion are added to 112.75 g of 3-cyano-4,7-dichlorophthalide and 96.7 g of 4,6-dimethoxy-2-methylsulfonyl-pyrimidine. (The hydride is washed with hexane, the hexane removed by suction and the residue covered with DMF and cooled it an ice bath.) The reaction mixture is left to stir overnight at RT and the solution then poured into 3 L of water containing 15 ml of conc. H2SO4 and stirred mechanically until a viscous gum formed around the stirred blade. The water layer is decanted and extracted with 3×400 ml of toluene, the first two extracts added to the gum and the mixture stirred until the gum dissolved. The toluene solution is washed 2×100 ml of water and 1×100 ml of toluene and the combined toluene layers dried over Na2SO4 concentrated to 400 ml and left to stand overnight. The still homogeneous solution is flash-chromatographed over silica gel with toluene (250 ml fraction 5) fractions 5-9 are combined and stripped to give 30 g of the title product m.p. 123°-126° C.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)([C:17]#[CH:18])[CH3:16]>C(N(CC)CC)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.[Cu]I>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:18]#[C:17][C:15]([N:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)([CH3:16])[CH3:14]
Reactant: C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc2c(c1I)OCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 30.4 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.290 g, 1.00 mmol) synthesized in Example B46, Step 2, dichlorobis(triphenylphosphine)palladium(II) (0.0702 g, 0.100 mmol) and copper(I) iodide (0.0190 g, 0.100 mmol) in triethylamine (4 mL) was added with a solution of tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (Journal of Medicinal Chemistry, Vol. 47, p. 2833, 2004, 0.252 g, 1.00 mmol) in triethylamine (4 mL), and the mixture was stirred at 50° C. for 7.5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate (0.126 g, 30%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([Cl:19])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CC(=O)O)c2c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2cccc(CC(=O)Cl)c2c1

Procedure:
The 7-methoxynaphth-1-ylacetic acid obtained above is dissolved, while warm, in 300 cm3 of chloroform. The mixture is heated to reflux, and then thionyl chloride is added dropwise. The mixture is refluxed for two hours and evaporated to dryness, yielding an oil which crystallises by cooling. The resulting residue is used as such in the following step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1.[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>C(O)C>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1)#[N:22]
Reactant: CSC(=NC#N)SC
Reactant: NCc1ncc(-c2csc(N=C(N)N)n2)s1
Solvent: CCO
Product: CSC(=NC#N)NCc1ncc(-c2csc(N=C(N)N)n2)s1

Procedure:
A mixture of 4-(2-aminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole (0.45 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N-CN] (0.26 g) in ethanol (10 ml) was refluxed for 5 hours with stirring to give 4-[2-(3-cyano-2-methylisothioureido)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole as a crude product. After cooling to ambient temperature, 40% aqueous methylamine by weight (1.4 ml) was added to the suspension and the mixture was stirred for 12 hours at ambient temperature. The solvent was evaporated in vacuo and the residue was mixed with water (5 ml) and ethyl acetate (5 ml). The resulting precipitate was collected and recrystallized from aqueous N,N-dimethylformamide to give 4-[2-(2-cyano-3-methylguanidino)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole (0.35 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[NH:4]1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:11]([N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[NH:4][CH:3]([CH:2]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH2:1])[CH2:9][C:8]1=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: NC(C(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Reaction time: 0.17 h

Procedure:
A solution of 4-(aminomethyl)-1-benzyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (0.99 g, 3.5 mmol) in 1,2-dichloroethane (15 mL) was cooled to 0° C., to which was added dropwise benzyl chloroformate (0.51 mL, 3.6 mmol). The mixture was stirred for 10 minutes at the same temperature, and for 25 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of l-benzyl-4-(benzyloxycarbonyl aminomethyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one. This crude product was dissolved in 1,2-dichloroethane (10 mL), to which was added phthalimidoacetyl chloride (0.79 g, 3.5 mmol). The mixture was stirred for 20 minutes at room temperature. To this solution was added 4-dimethylaminopyridine (DMAP) (43 mg, 0.35 mmol). The mixture was stirred for 25 minutes at room temperature, to which was further added DMAP (0.17 g, 1.4 mmol), and the mixture was stirred for 14 hours. To the reaction mixture was added water. The aqueous layer was separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, which was dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was recrystallized from chloroform-petroleum ether to afford the end product (1.42 g, 67%). m.p.219°-221° C.