Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)=[C:16]([NH:31][C:32]([C:34]3[S:35][CH:36]=[CH:37][C:38]=3[CH3:39])=[O:33])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(O)C.[OH-].[Na+]>C(O)C>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](/[CH:21]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][C:16]=2[NH:31][C:32]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])=[N:23]1
Reactant: Cc1ccsc1C(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1/C=C/c1n[nH]c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccsc1C(=O)Nc1cc(N2CCNCC2)ccc1/C=C/c1n[nH]c2ccccc12
Reaction time: 1 h
Yield: 55.1 %

Procedure:
(E)-4-{4-[2-(1H-indazol-3-yl)vinyl]-3-[(3-methylthiophene-2-carbonyl)amino]phenyl}piperazine-1-carboxylic acid tert-butyl ester (51 mg, 0.09 mmol) obtained in Step 4 was dissolved in ethanol (2.0 ml) and the solution was added with 1 mol/L hydrogen chloride-ethanol solution (1.0 mL), followed by stirring for 1 hour. To the reaction mixture under ice-cooling, 6 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture. Then the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in methanol to obtain Compound 274 (22 mg, 55%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:25](=[O:37])[NH:26][C:27]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29][CH:28]1[CH:30]=[CH2:31])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:35]([O:34][C:32]([C:27]1([NH:26][C:25]([CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14](=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)[CH2:10]2)=[O:37])[CH2:29][CH:28]1[CH:30]=[CH2:31])=[O:33])[CH3:36]
Reactant: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1)C(=O)OCC
Yield: 98 %

Procedure:
Compound 21b (11.84 g, 22.9 mmol) was deprotected in TFA (30 ml) dissolved in DCM (100 ml) and then worked up by methods known in the chemical art to give the title compound (9.37 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH2:35][CH:34]2[CH3:40].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:21]=1)=[O:27])[CH2:35][CH:34]2[CH3:40]
Reactant: CC1CNc2ccc(F)cc21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC(C)c5cc(F)ccc54)ncn3)CC1)C(=O)N2

Procedure:
80 mg (0.21 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 32 mg (0.21 mmol) 5-fluoro-3-methyl-2,3-dihydro-1H-indole, 70 μL (0.50 mmol) TEA and 74 mg (0.23 mmol) TBTU were stirred in 1.8 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH4+]=[S:2].[C:3]([CH:5]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:7]=1[F:16])#[N:4].C1COCC1.C(OCC)(=O)C>CO.O>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][CH:5]([C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:7]=2[F:16])[C:3]([NH2:4])=[S:2])=[CH:25][CH:24]=1)#[N:23]
Reactant: COc1cc(OC)c(F)c(C(C#N)Nc2ccc(C#N)cc2)c1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
After adding 14.2 ml of a 20% aqueous solution of ammonium sulfide to a solution of 2.59 g of 4-{[cyano-(2-fluoro-3,5-dimethoxyphenyl)methyl]amino}benzonitrile in 300 ml of a methanol:THF=2:1 mixed solvent, the mixture was stirred at room temperature for 16 hours. Then, a further 14.2 ml of a 20% aqueous solution of ammonium sulfide was added, and the mixture was stirred at room temperature for 24 hours. Next, 500 ml of ethyl acetate and 800 ml of water were added to the reaction mixture, and the organic layer was washed twice with 300 ml of water and then once with 300 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate (1:1)) to give the title compound (2.01 g) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.C(Cl)Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(NC(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[C:7](=[O:19])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:16][CH:17]=2)[CH2:9][CH:10]=1
Reactant: COC(=O)CCC1=CCN(Cc2ccc(N)cc2)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
10 mg of 3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (h) prepared by above Step 1 was dissolved in methylene chloride solution (0.04 mmol) at room temperature. And then 8.5 μl of benzoyl chloride (0.07 mmol) and 19.1 μl of diisopropylamine (0.11 mmol) were added thereto and the mixture was stirred for 2 hrs at 0° C. The reaction was quenched with methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with ethyl acetate and hexane (1:2) as an eluant to give 12 mg of 3-[1-(4-benzoylamino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (i) (yield: 87%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=O)[CH:17](Br)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]([NH2:35])=[S:34]>C(O)C.O>[NH2:35][C:33]1[S:34][C:17]([CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])=[C:16]([C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:32]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1C(=O)C(Br)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccc(Cl)cc2C(=O)c2ccccc2)c(CN2C(=O)c3ccccc3C2=O)s1

Procedure:
A stirred solution of 10 g (0.02 mole) of the end product of Example 2 and 2 g (0.026 mole) of thiourea in 60 ml of ethanol, protected by a drying tube, was refluxed for 1 hr. The yellow solution was poured over ice and diluted with water. The pale yellow solid was collected by filtration, washed with water and air dried on the funnel to give the end product. Recrystallization of a sample from methanol/methylene chloride solution gave pale yellow crystals: mp 253°-255° C.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[F:19])[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[F:19])[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3F)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cccc(F)c3F)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of 7-(1-azidoethyl)-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.083 g, 0.24 mmol) in tetrahydrofuran (3 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.29 mL, 0.29 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the crude product (0.076 g), which was used directly in next step. LCMS calculated for C15H14F2N3OS (M+H)+: m/z=322.1. Found: 322.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])C.B(O)(O)O.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([CH:7]=1)[NH:1][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([OH:23])=[O:12]
Reactant: Nc1cc(Cl)ccc1O
Reactant: CCOC(=O)CCCCCCC(=O)O
Agent: Cl
Agent: OB(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCCCCCC(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
8-(5-chloro-2-hydroxyanilino)-8-oxooctanoic acid was prepared as follows. A suspension of 2-amino-4-chlorophenol (17.88 g, 124.5 mmol), 8-ethoxy-8-oxooctanoic acid (25.19 g, 124.5 mmol), boric acid (0.385 g, 6.23 mmol) in 150 mL of dried toluene was heated at reflux (110° C.) under nitrogen for 4 hours during which water (2.5 mL) produced in the reaction was removed by azeotropic distillation in a Dean-Stark separation unit. The reaction was observed by thin layer chromatography on silica gel (Eluant: ethylacetate:heptane 1:1). The reaction mixture was cooled in a water bath to room temperature. 2N aqueous solution of sodium hydroxide (125 mL, 250 mmol) was added to the mixture. The mixture was heated at reflux for 4 hours. The reaction mixture was cooled in a water bath to room temperature. The mixture was then diluted with ethyl acetate (300 mL) and water (150 mL). The aqueous layer was washed with two portions of ethyl acetate (250 mL). After careful separation, the aqueous layer was chilled and acidified with a 10% (by weight) solution of hydrochloric acid (86.20 mL, 250 mmol) to yield a solid which was filtered, washed with hexane, and dried under vacuum. Trituration with dichloromethane yielded the desired acid (21.75 g, 57%) as an off-white solid. HPLC (Column: Higgins Kromasil 100 C18, water/acetonitile/acetic acid: 950/50/1, 3 mL/min, 220 nm) showed one single peak. Rt was 5.38 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:31])=[O:30])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[N:10]=1)(C)(C)[CH3:2].Cl.C(O)C>>[CH2:1]([O:5][C:6](=[O:45])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:31])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[N:10]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (120 mg, 0.184 mmol) obtained in Example 3-(a) was added a 6M hydrogen chloride/ethanol solution (1 ml), and the mixture was left at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (81.0 mg) as a colorless oil. (Yield: 84%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24].CO.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:18]([NH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])[CH:3]=1)(=[O:20])[CH3:19]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)NCCNc1cc(N)nc(-c2ccccc2)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
A solution of amine 5 was titrated with chloroacetyl chloride with monitoring by TLC (SiO2/8:1 and 14:1 DCM:MeOH) as follows: Neat chloroacetyl chloride (0.45 mL; 5.7 mmol) was slowly added down the side of a flask immersed in an ice-water bath into a solution of aminopyrimidine 5 (1.531 g; 5.64 mmol) and 2,6-lutidine (2.0 mL; 17 mmol) in DCM (30 mL) plus DMF (2.5 mL). Starting material remained so additional chloroacetyl chloride was added after 0.4 h (0.45 mL; 5.7 mmol) and again after an additional 0.5 h (90 μL; 1.1 mmol). After 0.5 h, EtOAc (150 mL) was added and the solution washed with saturated NaHCO3 (40 mL), 50% saturated NaCl (5×40 mL), saturated NaCl (2×40 mL), dried (MgSO4), filtered and concentrated to a yellow-orange crystalline solid. The crude material was triturated with hexanes (10 mL) then 1:1 hexanes:Et2O (2×10 mL) then purified on silica gel (250 mL) with 18:1 DCM:MeOH yielding a hard yellow foam (1.78 g; 91%). LC (method B) tR=13.5 min; 1H NMR (200 MHz, CDCl3) δ 8.70 (brs, 1H), 8.35 (m, 2H), 7.47 (m, 3H), 7.16 (s, 1H), 6.48 (brs, 1H), 5.59 (brt, 1H), 4.19 (s, 2H), 3.68 (m, 2H), 3.54 (m, 2H), 1.88 (s, 3H); ESIMS 347.9/349.9 (100/32) [MH+].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[N+:12]([O-])=[C:11]1[C:6](=[CH:7][C:8](=[O:23])[CH:9]=[CH:10]1)[O:5]2.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[OH-].[Na+]>[OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:12]=[C:11]1[C:6](=[CH:7][C:8](=[O:23])[CH:9]=[CH:10]1)[O:5]2
Reactant: COC(=O)CCc1cc2c(cc1O)oc1cc(=O)ccc-1[n+]2[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1cc2nc3ccc(=O)cc-3oc2cc1O
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Methyl ester (10a) (22.83 g, 72.4 mmol) was dissolved in 400 ml of 0.5 M aqueous sodium hydroxide and the solution was stirred for 1 h. A solution of sodium dithionite solution (200 ml, 100 mmol) was added and reaction mixture was stirred for additional 15 minutes. To precipitate the product 3 M hydrochloric acid (80 ml) was carefully added and resultant suspension was stirred for 10 min and centrifuged. The supernatant was decanted and the residue was re-suspended in ˜800 ml of water and centrifuged again. This operation was repeated one more time. Final supernatant had pH of 3–4. The centrifuged material was dried under vacuum overnight at 40° C. to afford 14.12 g (68%) of desired product (11a) as a brown solid. 1H NMR (CD3OD, +40° C.): δ 7.64 (d, J=9.0 Hz, 1H), 7.39 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.74 (s, 1H), 6.34 (s, 1H), 2.63 (m, 2H), 2.51 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8](Cl)[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4].[CH2:51]([SH:54])[CH2:52][CH3:53].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([S:54][CH2:51][CH2:52][CH3:53])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4]
Reactant: CCCS
Reactant: CCCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1c(=O)cc(SCCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Yield: 68 %

Procedure:
A mixture of 3-butyl-6-chloro-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (1.4 g), propylmercaptan (0.24 ml) and potassium carbonate (0.35 g) in acetonitrile (25 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (1 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccccn3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].O>O1CCCC1.C(Cl)Cl>[CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1c(C(=O)O)cccc1-c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1c(CO)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.4 %

Procedure:
To a stirred solution of 2-ethyl-[1,1'-biphenyl]-3-carboxylic acid (2.1 g, 0.0093 mole) in 50 ml of tetrahydrofuran was added dropwise borane-tetrahydrofuran complex (1.6 g, 0.0186 mole). The reaction mixture was stirred at room temperature for approximately 18 hours. Water (6 ml) was slowly added to the reaction mixture and the solvent removed under reduced pressure to give a residue. The residue was dissolved in methylene chloride; the solution was washed with 1N aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 2-ethyl-[1,1'-biphenyl]-3-methanol (2.1 g) as an oil. The ir and nmr spectra were consistent with the named compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.S(Cl)(Cl)=O.[N:13]1C=CC=[CH:15][CH:14]=1.Cl.C(N)C>CN(C=O)C.C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:14]([NH:13][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH3:15]
Reactant: c1ccncc1
Reactant: O=C(O)c1ccsc1
Agent: CCN
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccsc1
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of 3-thiophenecarboxylic acid (20 g, 178 mmol), thionyl chloride (30 mL), and DMF (5 drops) was stirred overnight, then was concentrated under vacuum and stripped several times from toluene to remove all traces of excess thionyl chloride. Pyridine (31.64 g, 400 mmol) was added dropwise to a mixture of this acid chloride and ethylamine hydrochloride in toluene (5 mL) and CH2Cl2 (50 mL). After stirring for 1 h, the reaction was washed with 10% aq HCl followed with water, then was dried (MgSO4), concentrated, and crystallized from ethyl acetate/hexanes to give 14.9 g of N-ethyl-3-thiophenecarboxamide as a tan solid, a 76% yield. m.p. 115°-117° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3](C)[CH:2]=1.[CH2:9]=O.[NH3:11]>>[NH3:11].[C:5]1([CH3:9])[C:6]([OH:7])=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: C=O
Reactant: Cc1ccc(O)cc1
Agent: N
Product: Cc1ccccc1O

Procedure:
A mixture of 1.0 mole of p-cresol, 1.2 moles of formaldehyde and 0.2 mole of ammonia is heated on a water bath to form an ammonia-cresol base resin. A quantity (40 parts) of this resin and 60 parts of a bisphenol-A type epoxy resin (Epikote® 1007 manufactured by Shell Chemical Company) are dissolved in a mixed organic solvent made up of equal amounts of methylisobutyl ketone and methylethyl ketone to form a base resin solution. Next, a maleic anhydride-modified olefin resin having 74.9% crystallinity and a degree of modification of 30.5 mg/100 g is dissolved in hot xylene to form a 10% solution. This solution is added to the base resin solution with sufficient agitation so that the amount of modified olefin resin added to the base resin is 20% (solids) based on the base resin. In this way, a primer coating composition or paint having a total solids content of about 30% is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.[F:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:35]4[CH2:34][CH2:33][N:32]([C:30](=[O:31])[C:29]5[CH:28]=[CH:27][C:26]([F:25])=[CH:39][CH:38]=5)[CH2:37][CH2:36]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Yield: 5 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (7.8 g, 0.02 mol) was added portionwise with stirring to a cold mixture of 1-(4-fluorobenzoyl)piperazine hydrochloride (4.9 g, 0.02 mol) in chloroform (250 ml) and sodium carbonate (24.4 g) in water (250 ml). The cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 hour the chloroform layer was separated and dried (MgSO4). The solvent was removed by evaporation to give a brown gum. Crystallisation from ethanol gave the pure title compound (0.53 g), m.p. 235°-237° C.