Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[C:22]1(B(O)O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cccc4ccccc34)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), naphthalene-1-boronic acid (99 mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in mixture of 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(naphthalen-1-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (DMSO, TFA salt) δ (ppm): 8.0 (d, 1H), 7.8 (d, 1H), 7.79 (d, 1H), 7.3-7.5 (m, 5H), 7.1 (s, 1H), 6.9 (d, 1H), 4.21 (m, 2H), 3.4 (m, 2H), 2.77-3.0 (m, 9H), 2.3 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Yield: 36 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-difluorophenyl isocyanate in a similar manner as described in Example 1.53, providing 26.7 mg (36%) of Compound 29: LCMS m/z (%)=395 (M+H37Cl, 35), 393 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 8.43 (s, 1H), 8.03 (m, J1=12 Hz, J2=4 Hz, 1H), 7.56 (s, 1H), 7.50 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.34 (d, J=4 Hz, 1H), 7.28 (m, J1=12 Hz, J2=4 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.01 (m, J1=8 Hz, J2=2 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[C:22]([O:26][NH:27][S:28]([CH:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]1=[C:38]=[O:39])(=[O:30])=[O:29])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:22]([O:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[S:28]([CH:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]1=[C:38]=[O:39])(=[O:30])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)ONS(=O)(=O)C1C=CC(Cl)=CC1=C=O
Reactant: COC(=O)CC[C@@H](CCCCO)CCCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CC[C@@H](CCCCN(OC(C)(C)C)S(=O)(=O)C1C=CC(Cl)=CC1=C=O)CCCc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of methyl (R)-8-hydroxy-4-[3-(3-pyridyl)propyl]octanoate (1.09 g 3.7 mmol), N-t-butoxy-carbonyl-p-chlorophenylsulfonamide (1.52 g, 5.2 mmol) and triphenylphosphine (1.92 g, 7.3 mmol) in methylene chloride (17 ml) is added dropwise diethyl azodicarboxylate (0.82 ml, 5.2 mmol). The reaction mixture is allowed to stir or 1 hour and the solvent is evaporated. The residue is purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane to obtain methyl (R)-8-[N-t-butoxy-carbonyl-p-chlorophenylsulfonamido]-4-[3-(3-pyridyl)propyl]octanoate; IR (CH2Cl2): 1730, 1356, 1154 cm- 1.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([OH:14])=O)[CH2:4]1.C([N:17](CC)CC)C.N>ClCCl>[N+:9]([O-:11])([O:8][C@H:7]1[CH2:6][C@H:5]([C:12](=[O:14])[NH2:17])[CH2:4][C@@H:3]1[O:2][CH3:1])=[O:10]
Reactant: CCN(CC)CC
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Agent: N
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](C(N)=O)C[C@@H]1O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a dichloromethane solution (30 mL) of (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylic acid (example 1, 0.13 g, 0.64 mmol) was added triethylamine (0.72 mL, 5.1 mmol) and ethyl chlorofonnate (0.49 mL, 5.1 mmol) at 0° C. The reaction solution was stirred at 0° C. for 1 hour when aqueous ammonia (8.0 mL, 0.10 mol, 28% wt) was added. The reaction was stirred for another 16 hours at 0° C. The aqueous phase was extracted with dichloromethane (2×15 mL). The combined organics were washed with cold 5% sodium bicarbonate (30 mL) and dried over magnesium sulfate. The organics were concentrated in vacuo and purified by column chromatography, affording the title compound as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 2.02 (ddd, J=3.7, 6.1, 14.5 Hz, 1H), 2.22 (dd, J=8.5, 15.3 Hz, 1H), 2.30-2.37 (m, 1H), 2.40-2.47 (m, 1H), 2.94 (quintet, J=6.2 Hz, 1H), 3.44 (s, 3H), 3.89-3.91 (m, 1H), 5.36 (d, J=6.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C([O-])([O-])=[O:26].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].O.C(O)(=O)C>CO.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:26])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Temperature: 10 °C
Reaction time: 15 h
Yield: 238.6 %

Procedure:
10 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazol were dissolved in 50 ml of methanol and 0.3 g of ammonium molybdate were added. The solution was cooled to 10° C., and 3.35 g of sodium percarbonate added slowly, kept stirred at the same temperature for 15 hours. After the reaction ended 250 ml of water were added and the pH of the resulting mixture adjusted to 10 with 10% acetic acid. This was kept stirred for 1 hour and the solid obtained was filtered, and subsequently washed with water and dried in a vacuum oven at 40° C. This provided 9.4 g of lansoprazol (yield: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]([C:12]([OH:14])=O)=[C:7]([C:9]([OH:11])=[O:10])[CH:8]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26]>>[O:26]=[C:20]1[CH:19]([N:18]2[C:12](=[O:14])[C:6]3[C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:15]2=[O:17])[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1cc(C(=O)O)c(C(=O)O)c(C(=O)O)c1
Product: COc1cc(C(=O)O)c2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 5-methoxy-benzene-1,2,3-tricarboxylic acid with 3-aminopiperidine-2,6-dione, in one embodiment, in the presence of a coupling reagent, to form 2-(2,6-dioxo-piperidin-3-yl)-6-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carboxylic acid;
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cccc(-c2cn3ccnc(Cl)c3n2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cccc(-c2nc3c(Cl)nccn3c2Br)c1

Procedure:
To the product from example 170 in acetic acid (10 mL) was added a solution of bromine in acetic acid (0.25 mmol, 1 mL). Concentration of the reaction mixture afforded crude 3-bromo-8-chloro-2-(3-methoxy-phenyl)-imidazo[1,2-a]pyrazine. MH+ (LCMS) 338.0(m/z).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[C:33]([CH3:41])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[C:33]([CH3:41])=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nn(Cc2ccccc2)c2cccc(N)c12
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3ccccc3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
A mixture of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.035 g, 0.148 mmol) in dichloromethane (10 mL) was added oxalyl chloride in dichloromethane (2M, 0.081 mL, 0.163 mmol) with a catalytic (drop) amount of DMF. After stirring at ambient temperature for 30 minutes, 1-benzyl-3-methyl-1H-indazol-4-amine (0.0387 g, 0.163 mmol) was added (as a solution in 1 mL methylene chloride), followed by diisopropylethylamine (0.0310 mL, 0.178 mmol). The mixture was stirred overnight and then partitioned between water and DCM. The combined organic extracts were dried (phase separator silicone treated filter paper), evaporated in vacuum and purified on silica gel (10-50% EtOAc in hexanes) to afford N-(1-benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.022 g, 33% yield) as a white solid, 22 mg. MS (APCI) m/z=456 (M+H).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][N:8]=1)=O>C(O)C>[Br:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:5][OH:4])[CH:12]=1
Reactant: COC(=O)c1cc(Br)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
Sodium borohydride (763 mg, 20.17 mmol) was added portionwise to a solution of 4-bromo-pyridine-2-carboxylic acid methyl ester (1.98 g, 9.166 mmol) in ethanol (50 mL) under nitrogen and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of acetone (10 mL) and the reaction was stirred for 15 minutes. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were collected, dried over anhydrous sodium sulfate and the solvent evaporated to afford the title compound (1.61 g, 94%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ3.4-3.5 (br s, 1H), 4.80 (s, 2H), 7.40 (dd, J=5.4, 1.8 Hz, 1H), 7.50 (br m, 1H), 8.39 (d, J=5.4 Hz, 1H). LCMS (m/z) 188/200 [M+H], Tr=1.55 min.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][NH2:28])[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH3:29][C:30](OC(C)=O)=[O:31]>N1C=CC=CC=1>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][NH:28][C:30](=[O:31])[CH3:29])[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To the solution of 2-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)ethanamine hydrochloride (Intermediate 19; 260 mg; 0.62 mmol) in pyridine (3 mL), was added Ac2O (2.00 mL; 2.13 mmol) under nitrogen. The reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue was trituated with a small amount of EtOAc to afford 150 mg (52%) of the title compound as a red solid, which was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[O:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: OC1CCOCC1
Product: Fc1ccc2c(c1)c(I)nn2C1CCOCC1
Yield: 56 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and tetrahydro-4-pyranol in 56% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.C1N2CN3CN(C2)CN1C3.[C:25](O)(=[O:27])C.Cl>O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:3][CH:4]=2)[C:9]=1[CH:25]=[O:27]
Reactant: COc1ccc2cc(CBr)ccc2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromomethyl-6-methoxynaphthalene (l2.68 g), hexamine (14 g), glacial acetic acid (21 ml) and water (21 ml) were heated under reflux with stirring for 30 minutes. Concentrated hydrochloric acid (16.6 ml) was then added and the mixture stirred and refluxed for a further 15 minutes. The reaction was cooled to room temperature and extracted with toluene (2×25 ml). The combined toluene extracts were washed with water (2×10 ml), saturated sodium bicarbonate solution (2×10 ml) and water (1×8 ml) and the toluene solution dried over MgSO4. The drying agent was filtered off and the solvent was removed by distillation under vacuum. This afforded 8.6 g of crude product which was recrystallised twice from isopropanol (2×50 ml) to give 6.07 g of 97.8% purity 2-methoxynaphthaldehyde as a light beige solid. The material had a melting point of 79.2° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[SH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>O>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:11][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1Sc1ccc2ccccc2c1

Procedure:
A well stirred mixture of 37.2 g. (0.15 mole) of o-iodobenzoic acid, 34.0 g. (0.15 mole) of 2-mercaptonaphthalene, 20.6 g. (0.15 mole) of potassium carbonate and 300 ml. of pyridine is heated at 50° C. for 1 hour, then 5 g. of cuprous chloride is added and the stirred mixture is heated at reflux for 18 hours. The mixture is poured into 1.2 liters of water and filtered. The filtrate is acidified and the resulting mixture is extracted into methylene chloride. The extracts are dried, concentrated, and the solid residue is recrystallized to give 2-(2-naphthylthio)benzoic acid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[C:9](O)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C>[Br:8][C:3]1[CH:4]=[C:5]2[C:6](=[CH:1][CH:2]=1)[O:7][C:9](=[O:18])[CH2:10][CH:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of p-bromophenol (138 g, 0.8 mole), cinnamic acid (148 g, 1.0 mole), acetic acid (200 g) and conc. sulfuric acid was refluxed for 2 h. Volatile material was distilled at reduced pressure. The residual syrup was cooled and triturated with cold water, giving a semi-crystalline mass. This was washed extensively with water, saturated sodium carbonate and finally with water again. The material was filtered through a sintered glass funnel, and then mixed with an equal weight of ethanol. The slurry was stirred at room temperature for 1 h and then filtered. The resulting product was washed briefly with ethanol and then diisopropyl ether. After drying, 135 g (55.7%) of the title compound was isolated as white crystals, melting at 117° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:8](Cl)[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:23])[CH:21]=[CH2:22]>O>[CH2:20]([NH:23][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=1)[CH:21]=[CH2:22]
Reactant: CCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NCCCC)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To 170 mg (0.67 mmol) of 4-butylamino-2-chloro-6-nitroquinazoline was added 1.52 g (26.66 mmol) of allylamine, followed by stirring at room temperature overnight. To the reaction solution was water added, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 166 mg (yield: 82.1%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)c1cnc2n(c1=O)CCc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2n(c1=O)CCc1ccccc1-2
Yield: 63 %

Procedure:
A mixture of ethyl 6,7-dihydro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.81 g., 6.7 mmoles), 1.0 N NaOH (25 ml.) and 95% ethanol was refluxed for 20 l minutes. The resulting solution was cooled and acidified with 1.0 HCl (26 ml.) to precipitate the acid, which was crystallized from 2-methoxyethanol to give colorless crystals: 1.02 g. (63% yield), m.p. 215°-217°. An additional recrystallization from 2-methoxyethanol gave material with m.p. 215.5°-217°.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[NH:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[C:22]([OH:24])=[O:23].C[O-].[Na+].CN(C)C=O.Cl[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>O>[OH:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:16]=[C:14]1[C:15]2[C:2]([NH2:1])=[C:3]([C:22]([OH:24])=[O:23])[C:4]([C:19]([OH:21])=[O:20])=[C:5]([NH2:18])[C:6]=2[C:7](=[O:17])[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: OCCCCCCCl
Reactant: N=C1c2ccccc2C(=O)c2c(N)c(C(=O)O)c(C(=O)O)c(N)c21
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(C(=O)O)c(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=NCCCCCCO
Temperature: 100 °C

Procedure:
A mixture of 9.2 g of 1,4-diaminoanthraquinone-2,3-dicarboxylic acid imide, 1.8 g of sodium methylate and 50 g of dimethylformamide is heated to 100° C., 4.9 g of 6-chlorohexan-1-ol are added, the mixture is heated at 100° C. for 3 hours, allowed to cool and poured onto 300 g of water, and the precipitated product is filtered off under suction, washed with water, dried and then recrystallized from 1,1,2-trichloroethane.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([O:19]CC)=[O:18])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.O.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([OH:19])=[O:18])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ncc(OC)c2c1CCN(Cc1ccc(F)cc1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(C(=O)O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (1.21 g, 3.38 mmol) in methanol (5 mL) and water (5 mL) and THF (5 mL) was added lithium hydroxide (0.425 g, 10.13 mmol). After 5 minutes, 1N HCl (3 equiv.) was added to the product mixture, which was then dried under vacuum to provide the crude title compound.
Reaction SMILES: COC1C=CC([N:9]([C:14](=O)[C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24][CH2:25][O:26][CH3:27])=[CH:17][C:16]=2[O:28][CH2:29][O:30][CH3:31])[NH:10][C:11]([NH2:13])=[S:12])=CC=1.[Cl-].[NH4+]>[OH-].[Na+]>[CH:21]([C:19]1[C:18]([O:24][CH2:25][O:26][CH3:27])=[CH:17][C:16]([O:28][CH2:29][O:30][CH3:31])=[C:15]([C:14]2[N:13]([C:15]3[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[CH:17][CH:16]=3)[C:11](=[S:12])[NH:10][N:9]=2)[CH:20]=1)([CH3:23])[CH3:22]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)N(NC(N)=S)c1ccc(OC)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(OC)cc1
Yield: 171.4 %

Procedure:
4-methoxyphenyl-1-[5-isopropyl-2,4-bis(methoxymethoxy)-benzoyl]thiosemicarbazide (F53-03: 24.9 g, 53.7 mmol) and 5% aqueous sodium hydroxide (500 mL) were placed in a 1 L eggplant shaped flask and heated under reflux for 1 hour. After completing the reaction, the reaction mixture was neutralized with saturated aqueous ammonium chloride, and the solids deposited were collected by filtration, washed with distilled water and then dried under reduced pressure. The crude product thus obtained was purified by suspending in ethyl acetate/hexane and concentrating under reduced pressure to obtain the title compound (F53-04:20.5 g, 85.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15]CC>>[CH2:10]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(O)CO
Reactant: COc1cscc1OC
Product: CCCCCCC1COc2cscc2O1

Procedure:
Racemic 2-n-hexyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with racemic 1,2-octanediol as described in EXAMPLE 1. It was characterized by GC-MS and 1H-NMR-spectroscopy, and exhibited no optical rotation.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=359.