Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[C:17]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: CC(C)(C)c1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-tert-butylaniline gave N2-(3-tert-butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 23.82 min.; purity: 100%; MS (m/e): 353 (MH+); 1H NMR (CDCl3): δ 7.96 (1H, d, J=3 Hz), 7.61 (1H, ddd, J=7.5, 2.2 and 0.9 Hz), 7.49 (1H, t, J=2.5 Hz), 7.27 (1H, m), 7.18 (1H, t, J=8.1 Hz), 7.99 (1H, m), 6.94 (1H, s), 6.91 (1H, dd, J=7.5 and 2.5 Hz), 6.80 (1H, d, J=7.5 Hz), 6.72 (2H, m), 6.58 (1H, ddd, J=7.5, 2.5 and 0.9 Hz), 6.52 (1H, ddd, J=7.5, 2.5 and 0.9 Hz), 1.28 (9H, s).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6].C(CCCC[Sn]([O:28][CH2:29][CH3:30])(CCCC)CCCC)=C>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.C1(C)C=CC=CC=1>[C:29]([C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6])(=[O:28])[CH3:30]
Reactant: C=CCCCC[Sn](CCCC)(CCCC)OCC
Reactant: COc1ccc(Br)c(C)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)=O)c(C)c1C#N
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a 20 mL microwave tube was added a stir bar, 3-bromo-6-methoxy-2-methylbenzonitrile (4.0 g, 18 mmol), vinyl ethoxy tributyltin (9.5 g, 26 mmol), palladium tetrakis (1.0 g, 0.88 mmol), and anhydrous toluene (15 mL). The tube was capped, degassed and purged with N2. The reaction mixture was heated to 110° C. for 12 hours. The tube was cooled to room temperature and treated with 4 M HCl (10 mL) and stirred for 1 hour. The crude product was extracted with EtOAc. The extraction was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (Hexanes:EtOAc=1:1) to afford the title product.
Reaction SMILES: [NH2:1][CH:2]([CH:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)[CH3:6])[C:3]#[N:4].C(N)CN>CO.[Ni]>[N:12]1[C:13]2[C:8](=[C:7]([CH:5]([CH3:6])[CH:2]([NH2:1])[CH2:3][NH2:4])[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(c1cccc2ncccc12)C(N)C#N
Agent: [Ni]
Solvent: CO
Solvent: NCCN
Product: CC(c1cccc2ncccc12)C(N)CN
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.3 %

Procedure:
In a Parr bottle, a mixture of 2-amino-3-quinolin-5-yl-butyronitrile (Intermediate-E2) (5.38 g, 25.4 mmol) in MeOH (100 mL) and ethylene diamine (3.2 mL, 47.8 mmol) was reacted with Raney 2800 nickel (18.9 g) and bubbled with ammonia gas for 10 m. The Parr bottle was pressurized with hydrogen at 50 psi and shaken on a Parr apparatus for 2.5 h at rt. The mixture was filtered through celite, washed with MeOH (3×) and evaporated to leave a residue. This material was placed onto a column and eluted with a gradient of 1% to 5% sat. NH3-MeOH:CH2Cl2 to give 3-quinolin-5-yl-butane-1,2-diamine (Intermediate E3) 3.9 g (71%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:18]=1[C:19](Cl)=[O:20]>O1CCCC1.Cl.C(N(CC)CC)C>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:18]=1[C:19]([N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2])=[O:20]
Reactant: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: CCc1nc(C)c[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(C)cn1C(=O)c1c(Cl)cccc1[N+](=O)[O-]

Procedure:
15.4 g of 2-ethyl-4-methyl-imidazole are dissolved in 100 ml of tetrahydrofuran; 14.6 g of triethylamine are added, and there can then added dropwise, within 30 minutes at reflux temperature, 30.8 g of 2-chloro-6-nitrobenzoyl chloride, dissolved in 50 ml of tetrahydrofuran, in the process of which triethylamine hydrochloride precipitates. After 3 hours of refluxing, the mixture is filtered with suction, and the solvent is removed in the rotary evaporator. Recrystallisation of the residue from 85 ml of toluene yields 27.7 g (67.3% of theory) of the desired product, m.p. 119°-120° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:21]3[CH:22]=[C:23]4[CH2:28][CH2:27][CH2:26][C:24]4=[CH:25][C:20]=3[O:19][C:18](=[O:29])[C:17]=2[C:30]([O:32]CC)=[O:31])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[C:21]3[CH:22]=[C:23]4[CH2:28][CH2:27][CH2:26][C:24]4=[CH:25][C:20]=3[O:19][C:18](=[O:29])[C:17]=2[C:30]([OH:32])=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc3c(cc2oc1=O)CCC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(-c2c(C(=O)O)c(=O)oc3cc4c(cc23)CCC4)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylate (1.85 g), potassium hydroxide (1.12 g) and 80% ethanol (12 ml) was stirred at room temperature for 3 hours. The reaction mixture was then diluted with water, adjusted to pH4 with 6N HCl and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give crystals of 4-(3,5-di-tert-butyl-4-hydroxyphen-yl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-carboxylic acid. The crystals were collected by filtration and washed with isopropyl ether (1.13 g, 64.9%). mp. 256°-260° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[C:37]([NH:15][C:13]([C:11]1[C:10]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[CH:22][CH:23]=2)=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1)=[O:14])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(N)=O)cc1
Product: CC(=O)NC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Yield: 48 %

Procedure:
A mixture of 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxamide (0.50 g) and acetic anhydride (20 mL) was heated under reflux for 4 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine and concentrated to give N-acetyl-1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxamide as colorless crystals (0.25 g, yield 48%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 193-194° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.Cl.[CH:16]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[CH:16]1([N:24]2[C:2]3[N:7]4[N:8]=[CH:9][N:10]=[C:6]4[N:5]=[C:4]([CH3:11])[C:3]=3[CH2:12][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCCCC1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c2c1CCN2C1CCCCCCC1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 1.45g of cyclooctylamine hydrochloride, 4 ml of triethylamine and 20 ml of isopropyl alcohol was stirred under reflux for 1.5 hours, and treated thereafter as described in Example 5. The crystals thus obtained were recrystallized from ethanol to give 1.25g of colorless needles of m.p. 188.5° - 190.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][C:4](=O)[CH2:3]1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].[Cl-].[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[C:9](/[C:11](=[C:4]1\[CH2:3][C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5]\1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: CC1(C)CCC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C1\CCC(C)(C)C1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with a stir bar, reflux condenser, and Dean Stark trap were added 3,3-dimethylcyclopentanone (3.4 g, 30 mmol), toluene (50 mL), and ethyl 2-cyanoacetate (3.4 g, 30 mmol), ammonium chloride (231 mg, 3 mmol) and acetic acid (0.36 mL, 6 mmol). The reaction mixture was refluxed for 24 h. The reaction was cooled to RT and concentrated to dryness. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were dried with Na2SO4, concentrated to dryness subjected to FCC to afford the title compound as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:8]([O:10][CH3:11])[CH:9]=1)([O-])=O.[OH-].[Na+]>C(O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=1[S:12]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)ccc1S(=O)(=O)c1ccncc1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
A stirred solution of 5-nitro-2-(4-pyridylsulfonyl)anisole (3.00 g, 10.2 mmol) and stannous chloride dehydrate (11.49 g, 51.0 mmol) in absolute ethanol (35 mL) was heated at reflux for 1 hour. The reaction mixture was poured into ice water, and the aqueous solution basified with 15% NaOH and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried (MgSO4) and the solvent removed in vacuo to yield the title benzeneamine as a pale yellow solid (2.23 g, 83%); mp 150°-152° C. 1H--NMR (250 MHz, d6--DMSO): 3.62 (s, 3H, OCH3) 6.18 (d, 1H, J=1.8 Hz, aromatic) 6.24 (d, 1H, J=1.9 Hz, aromatic) 6.28 (s, 2H, NH2) 7.58 (d, 1H, J=8.8 Hz, aromatic) 7.70 (dd, 2H, J=4.5, 1.5 Hz, aromatic) 8.79 (dd, 2H, J=4.4, 1.6 Hz, aromatic). MS (CI, CH4): 265 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:8]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)sc1Cl)C2
Temperature: 100 °C
Reaction time: 14 h
Yield: 176.9 %

Procedure:
A mixture of 7-(2,5-dichlorothiophene-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (218 mg), aminoguanidine hydrochloride (83 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (4 ml) was stirred at 100° C. (bath temperature) for 14 hours. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2,5-dichlorothiophene-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 102) (250 mg) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C@@H:26]([CH2:28][OH:29])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C@H:26]([CH3:27])[CH2:28][OH:29])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)CO
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N[C@H](C)CO)cn1
Yield: 94 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using D-alaninol instead of 2-amino-2-methyl-1-propanol, to the title compound (100 mg, 94%) which was obtained as a white solid. MS: m/e=402.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1Cl)[CH3:2].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22]1)[CH3:2]
Reactant: CCOCCn1c(Cl)nc2ccccc21
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOCCn1c(NC2CCN(C(=O)OCC)CC2)nc2ccccc21
Temperature: 170 °C
Reaction time: 12 h

Procedure:
Combine 1-(2-ethoxyethyl)-2-chloro-1H-benzimidazole (3.06 g, 13.62 mmol) and ethyl 4-aminopiperidine-1-carboxylate (5.16 g, 30 mmol) and heat to 150° C. After 12 hours, heat to 170° C. After 8 hours, cool the reaction mixture and partition between dichloromethane (150 mL) and water. Separate the layers and extract the organic layer with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate/hexane 1/1 to give (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonyl-piperidin-4-yl)amine: Rf=0.15 (silica gel, ethyl acetate/hexane).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:18])[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1
Reactant: Cc1csc([C@H](N)Cc2c[nH]c3ccccc23)n1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1csc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (R)-2-(1H-indol-3-yl)-1-(4-methylthiazol-2-yl)ethylamine (500 mg, 1.94 mmol) and 4-dimethylamino-4-phenylcyclohexanone (421 mg, 1.94 mmol) in anhydrous tetrahydrofuran (40 mL) was mixed with sodium sulphate (1.00 g) and stirred for 3 h at room temperature. After adding, acetic acid (291 mg, 287 μL, 4.85 mmol), sodium triacetoxyboron hydride (574 mg, 2.71 mmol) was added and the mixture stirred overnight at room temperature. The mixture was then filtered, the filtrate concentrated to low volume in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (876 mg) was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol [95:5→9:1 and 1% ammonia in each case (33% in water)]. The non-polar diastereoisomer (450 mg) was purified once again by flash chromatography (38 g, 20×2.5 cm) with dichloromethane/methanol (300:9) and 1% ammonia (33% in water). The polar diastereoisomer (262 mg) was also purified once again by flash chromatography (18 g, 20×2.0 cm) with dichloromethane/methanol (24:1) and 1% ammonia (33% in water).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:27]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:27])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3.00 g (8.95 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2a) in 30 mL of DCM is added 1.26 mL (13.4 mmol) phosphorus tribromide at 0° C. The cooling bath is removed, the mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous layer is washed three times with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: C[C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18]C)=[O:16])[C:5]=2[C:4](=[O:23])[O:3]1.C[O-].[Na+]>CO>[OH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]2[CH:22]=[CH:21][CH:20]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[C:5]=1[C:4]([O:3][CH3:2])=[O:23]
Reactant: CCOC(=O)c1cccc(-c2cccc3c2C(=O)OC(C)(C)O3)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc(O)c2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a solution of 3-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl)benzoic acid, ethyl ester (1.4 g, 4.3 mmol) in methanol (10 mL) was added sodium methoxide (0.5 M in methanol, 25 mL) at 0° C. The solution was stirred at room temperature for 15 minutes. The reaction was quenched by addition of 1 N HCl (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over MgSO4 and concentrated to afford 3-hydroxy-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.2 g, 95%) as a yellow solid: 1H NMR (CDCl3) δ 3.43 (s, 3H), 3.93 (s, 3H), 6.79 (dd, J=7.5, 0.9 Hz, 1H), 7.04 (dd, J=7.5, 0.9 Hz, 1H), 7.43 (m, 3H), 7.93 (m, 1H) 8.02 (dm, J=7.0 Hz, 1H), 10.8 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC(N(C)C)=O.CCOC(C)=O>[O:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1nc(N2CCOCC2)cc(N2CCOCC2)n1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
4,6-dimorpholinopyrimidin-2-amine was prepared using the following procedure: 2-amino-4,6-dichloropyrimidine (1 g, 6.10 mmol) and morpholine (5.33 ml, 60.9 mmol) were dissolved in DMA (1.1 ml) and sealed into a microwave tube. The mixture was heated to 150° C. over a period of 20 minutes in the microwave reactor. The reaction mixture was diluted with AcOEt, filtered and the filtrate concentrated to give an oil. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 4,6-dimorpholinopyrimidin-2-amine (1.15 g, 71%) as a white foam.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]1(=[O:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[O:19]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:3]([O:6][CH3:7])=[O:8]
Reactant: O=C1CCCc2ccccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Under an argon atmosphere, a mixture of sodium hydride (60% dispersion in mineral oil, 887 mg, 22.0 mmol), dimethyl carbonate (15 mL) and 3,4-dihydronaphthalen-1(2H)-one (1.46 g, 10.0 mmol) was stirred at 80° C. for 3.5 hr. The reaction mixture was quenched with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium carbonate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/0-5/1) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](O)[C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: Cc1ccc(C(=O)NC(O)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC(Cl)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A stirred solution of Example 1A (3.48 g, 15.0 mmol) in CH2Cl2 (60 mL) at 0° C. was treated with pyridine (1.20 mL). The reaction mixture was treated dropwise with thionyl chloride (1.10 mL, 15.0 mmol), and the reaction flask was equipped with a calcium chloride drying tube. The reaction mixture was stirred at 0° C. for 4 hours, the cooling bath was removed, and the solution was stirred at ambient temperature for an additional 12 hours. Concentration of the reaction mixture provided a white solid which was triturated with diethyl ether (2×200 mL) to provide 2.40 g of the desired product as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]3)=[CH:4][C:3]=1[C:29]([CH3:32])([CH3:31])[CH3:30].[OH:33]O>>[OH:1][C:2]1[C:3]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][C:5]([S:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]3)=[O:33])=[CH:6][C:7]=1[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc(C(C)(C)C)c1O
Reactant: OO
Product: CC(C)(C)c1cc(S(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)cc(C(C)(C)C)c1O

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-hydroxy-3,5-di-tert. butylphenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:25]3[CH2:26][CH2:27][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)on2)cc1
Yield: 67.3 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-phenylpiperazine (7.6, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0. 15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16 hr and followed the same processes as in Example 1 to obtain 11.7 mg (67.3%) of the target compound.