Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[K+].[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[C:19]([CH3:39])[CH:18]=1.C(O)C>C(#N)C.C(OCC)C>[CH3:39][C:19]1[CH:18]=[C:17]([NH:16][C:13]([NH:14][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[S:12])[CH:38]=[CH:37][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH:23]=1
Reactant: Cc1cc(N)ccc1Oc1ccnc(NC(=O)N2CCOCC2)c1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc(NC(=S)NC(=O)Cc2ccc(F)cc2)ccc1Oc1ccnc(NC(=O)N2CCOCC2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a solution of 2-(4-fluorophenyl)acetyl chloride (63.2 mg) in acetonitrile (30 ml) was added potassium thiocyanate (35.6 mg), followed by stirring under a nitrogen atmosphere at 50° C. for 1 hr. The reaction mixture was cooled down to room temperature, and then morpholine-4-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridine-2-yl]amide (80 mg) was added thereto, followed by stirring under a nitrogen atmosphere for 2 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (60 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:5, then ethyl acetate). Fractions containing the target compound were concentrated to give an oil, which was then added in diethyl ether concentrated under a reduced pressure again to give a solid. The resultant solid was then suspended in diethyl ether (4 ml)-ethanol (0.4 ml), filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (14 mg, 11%) as colorless powder.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[N:13]1([CH:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:21][CH2:20]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[N:13]1([CH:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][N:52]=[C:26]34)[CH2:21][CH2:20]2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogen carbonate (0.38 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(4-morpholin-4-ylcyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.043 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was adjusted to pH 7 with 1 N hydrochloric acid and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.025 g, 20%).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([O:7][CH2:8][CH2:9][SH:10])[O:3][CH2:4][CH2:5][SH:6].C(N(CC)CC)C.ClC([SiH2][C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1)Cl.SCCO>CCOCC>[CH3:1][Si:2]([C:11]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)([O:3][CH2:4][CH2:5][SH:6])[O:7][CH2:8][CH2:9][SH:10]
Reactant: ClC(Cl)[SiH2]c1ccccc1
Reactant: C[Si](C)(OCCS)OCCS
Agent: OCCS
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](OCCS)(OCCS)c1ccccc1

Procedure:
The 2-[methyl-phenyl-(2-sulfanylethoxy)silyl]oxyethanethiol (4) composition was synthesized according to the same procedure as 2-[dimethyl(2-sulfanylethoxy)silyl]oxyethanethiol (1), using triethylamine (5.02 g, 0.050 mol), dichloromethylphenylsilane (4.74 g, 0.025 mol), and 2-mercaptoethanol (3.88 g, 0.050 mol) in ether (500 mL). The 2-[methyl-phenyl-(2-sulfanylethoxy)silyl]oxyethanethiol (4) composition was obtained as a clear, colorless, foul-smelling liquid (6.30 g, 92.6%). The product was purified by distillation under reduced pressure and obtained as a clear, colorless, foul-smelling liquid (3.70 g, 54.4%), Bp=140-142° C. at 0.50 mmHg.
Reaction SMILES: C[C@@]12[C@@H](C(NC3C=C(C(F)(F)F)C=CC=3C(F)(F)F)=O)CC[C@H]1[C@@H]1CC[C@H]3NC(=O)C=C[C@]3(C)[C@H]1CC2.[O:38]=[C:39]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C:41]([CH2:42][CH2:43][C@@H:44]3[C@@H:53]2[CH2:52][CH2:51][C@@:49]2([CH3:50])[C@H:45]3[CH2:46][CH2:47][C@@H:48]2[C:58]([OH:60])=O)=[CH:40]1.S(Cl)([Cl:63])=O>N1C=CC=CC=1>[O:38]=[C:39]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C:41]([CH2:42][CH2:43][C@@H:44]3[C@@H:53]2[CH2:52][CH2:51][C@@:49]2([CH3:50])[C@H:45]3[CH2:46][CH2:47][C@@H:48]2[C:58]([Cl:63])=[O:60])=[CH:40]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: O=S(Cl)Cl
Agent: C[C@]12C=CC(=O)N[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)Nc3cc(C(F)(F)F)ccc3C(F)(F)F)CC[C@@H]12
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl

Procedure:
U.S. Pat. No. 5,565,467 disclosed Dutasteride and process for preparation. According to U.S. Pat. No. '467, Dutasteride may be prepared by reacting 3-oxo-4-androstene-17β-carboxylic acid (II) with thionyl chloride in presence of pyridine to produce 3-oxo-4-androstene-17β-carboxylic acid chloride (IIa), which is further reacted with 2,5-bis(trifluoromethyl)aniline (III) to produce 17β-N-[2,5-bis(trifluoromethyl)-phenyl]carbomoyl-1-androst-4-en-3-one (IV). Oxidation of 17β-N-[2,5-bis(trifluoromethyl)phenyl]carbomoyl-1-androst-4-en-3-one (IV) by treating with aqueous sodium permanganate and sodium periodate under basic conditions produce 17β-N-[2,5-bis(trifluoromethyl)phenyl]carbamoyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid (V), which is further treated with ammonia in ethylene glycol, followed by hydrogenation to produce 17β-N-[2,5-bis(trifluoromethyl)phenyl]carbamoyl-4-aza-5α-androstan-3-one (VI). Dehydrogenating a compound (VI) using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide in dry dioxane to produce Dutasteride (I).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>O1CCCC1.C([Li])CCC>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:21]([C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)[OH:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(C=O)o1
Reactant: CSc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)c2cc3cc(SC)ccc3n2S(=O)(=O)c2ccccc2)o1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 1-benzenesulfonyl-5-methylthioindole (0.5178 g) in tetrahydrofuran (17 ml), n-butyl lithium (1.3 ml, 1.59 M) was added dropwise at −78° C. and the mixture was stirred for 30 minutes, followed by addition of the compound obtained in Example 30 (1) (0.3444 g), and the mixture was stirred at −50° C. for 40 minutes. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.593 g of the desired product.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:31])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[N:11]([S:32]([C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])(=[O:34])=[O:33])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH2:29]([O:28][C:26](=[O:27])[C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][CH2:9][CH2:10][N:11]3[S:32]([C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])(=[O:34])=[O:33])=[O:31])=[CH:21][CH:22]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3)cc1

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (95 mg, 0.15 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature 2 hours. The volatiles were removed and the residue was purified by trituration in dichloromethane. 4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoic acid ethyl ester was obtained as a white solid, 61 mg (76%), MS (ISP): m/e=530.3, 532.3 (M+H+.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)[C:10]2([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.O.NN>CO>[NH2:23][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]1([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(c2ccc(F)c(Cl)c2)N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(C(N)c2ccc(F)c(Cl)c2)C1
Temperature: 60 °C
Yield: 92.3 %

Procedure:
To a stirred solution of 79 (238.5 mg, 0.500 mmol) and THF:MeOH (5.0 mL 1:1) was added hydrazine monohydrate (242.6 μL, 5.001 mmol) and the solution was heated to 60° C. for 16 h. The reaction was then cooled to RT and concentrated in vacuo. The residue was diluted with EtOAc and washed sequentially with water (1×), NaHCO3 (1×), and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo to afford 160.1 mg (92.3%) of tert-butyl 3-(amino(3-chloro-4-fluorophenyl)methyl)-3-fluoropyrrolidine-1-carboxylate (78).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[NH:27][CH:26]=[C:25]([C:28]([O:30]C)=[O:29])[CH:24]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8].C1COCC1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[NH:27][CH:26]=[C:25]([C:28]([OH:30])=[O:29])[CH:24]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: COC(=O)c1c[nH]c(-c2cc(Nc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccoc1C(=O)Nc1cccc(Nc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Temperature: 60 °C

Procedure:
To a stirred solution of methyl 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylate (10 mg, 0.024 mmol) in a mixture of solvents THF/MeOH (5 ml/5 ml) was added 2 ml of 1M NaOH (2 mmol) solution. The mixture was heated in a 60° C. bath for 16 hours, cooled to room temperature and poured into 100 ml of water. 2M HCl was added until pH=5. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-[4-({3-[(3-methyl-2-furoyl)amino]phenyl}amino)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid as light brown solid. Yield: 2 mg.
Reaction SMILES: [OH-].[Na+:2].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[C:11](=[S:13])=[S:12]>O.CCO>[C:3]([C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([S-:13])[S-:12])#[N:4].[Na+:2].[Na+:2]
Reactant: CCOC(=O)CC#N
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C#N)=C([S-])[S-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
A solution of NaOH (40 g, 999 mmol) in H2O (40 mL) was slowly added via an addition funnel such that the internal temperature did not exceed 10° C. to a cold (0° C.) solution of ethyl 2-cyanoacetate (53.3 mL, 499.5 mmol) and carbon disulfide (30.2 mL, 499.5 mmol) in absolute EtOH (600 mL) Once the addition was complete, the reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was then cooled to 5° C. The resulting solids were isolated by filtration and washed with EtOH (100 mL), ether (500 mL) and dried in vacuo to give sodium 2-cyano-3-ethoxy-3-oxoprop-1-ene-1,1-bis(thiolate) (110.0 g, 97%) as a solid.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:29])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH2:20].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:16][O:17][C:18](=[O:29])[CH:19]([NH:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: O=C1CCCCC1C(=O)c1cccnc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: COc1ccccc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
To a mixture of 2-nicotinoylcyclohexanone (914.0 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-((2-nicotinoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (58.6 g, 39.0%).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][NH2:57])[N:51]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:52]4[N:51]=[N:50][CH:55]=[CH:54][CH:53]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: NCc1cccnn1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnn1
Yield: 52 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridazin-3-ylmethanamine, the title compound was obtained as a colorless solid in 52% yield: mp 222-225° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.15 (dd, J=4.8, 1.6 Hz, 1H), 8.67 (t, J=5.7 Hz, 1H), 7.71-7.66 (m, 1H), 7.62-7.59 (m, 1H), 7.40-7.35 (m, 2H), 7.24-7.18 (m, 2H), 4.69 (d, J=5.7 Hz, 2H), 4.44 (s, 2H), 4.05-4.00 (m, 2 H), 3.50-3.45 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.[CH3:28]C(OC)(C)C>C1COCC1>[Br:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:22][CH:21]=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([C@@H:24]2[CH2:28][C@H:11]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(C)(C)C
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 97.5 %

Procedure:
The trans t-butyl 3-(4-bromophenyl)acrylate was prepared as follows: A flame dried three-neck flask equipped with a thermometer, an addition funnel and a N2 inlet was charged with NaH (3.96 g, 99.1 mmol, 1.1 eq.) and anhydrous THF (120 mL). With moderate stirring under N2, a solution of t-butyl diethylphosphonoacetate (23.2 mL, 99.1 mmol, 1.1 eq.) dissolved in anhydrous THF (20 mL) was charged dropwise via addition funnel over a period of 30 min. The resulting mixture changed from a slurry to a clear, light yellow colored solution. An exotherm from 25° C. to 35° C. was observed during the addition. After completing the addition, the solution was stirred at RT for 30 min. A solution of 4-bromobenzaldehyde (15.9 g, 86.1 mmol, 1.0 eq) dissolved in anhydrous THF (20 mL) was charged to the above solution dropwise via the addition funnel over a period of 30 min. An exotherm from 25° C. to 35° C. was observed. The reaction mixture was stirred at RT for 1 h. The reaction mixture was analyzed for completion using 1H NMR. The reaction mixture was diluted by the sequential addition of MTBE (200 mL) and sat. NH4CI (150 mL). The organic layer was separated and washed with H2O (25 mL), and sat. NH4Cl (25 mL). After drying over MgSO4, the organic layer was evaporated to dryness to give 23.7 g desired product as a white solid (97.5% yield). 1H NMR (400 MHz, CDCl3-d) δ ppm 1.55 (s, 9H) 6.38 (d, 1H) 7.39 (d, 2H) 7.45-7.59 (m, 3H).
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[CH3:29]O>C(OCC)C.O1CCCC1>[CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]([O:27][CH3:29])=[O:26])=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCc1cc2cc(C(=O)OC)ccc2[nH]1

Procedure:
A solution of 2-(n-pentadecyl)indole-5-carboxylic acid (15.0 g) in methanol (100 ml) containing aqueous hydrochloric acid (10 ml, of strength 36.5% w/v) was refluxed for 5 hours. After cooling, the mixture was dissolved in a mixture of diethyl ether and tetrahydrofuran (1:1). The solution was washed with water (2×50 ml), dried over sodium sulphate, evaporated in vacuo, and the residue was recrystallised from methanol to give methyl 2-(n-pentadecyl)indole-5-carboxylate (12.2 g), in the form of an off-white powder, m.p. 89°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([P:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[O:9]CC)[CH:5]=[CH:6][CH:7]=1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41]Br.[CH2:43](Br)[CH3:44]>CC1C=CC=CC=1C>[F:1][C:2]1[CH:3]=[C:4]([P:8]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][C:32]=2[CH2:41][P:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])([C:44]2[CH:43]=[CH:12][CH:13]=[C:14]([F:18])[CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(c1cccc(F)c1)c1cccc(F)c1
Reactant: CCBr
Reactant: BrCc1ccc2ccccc2c1-c1c(CBr)ccc2ccccc12
Solvent: Cc1ccccc1C
Product: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2cccc(F)c2)c2cccc(F)c2)ccc2ccccc12)(c1cccc(F)c1)c1cccc(F)c1
Temperature: 0 °C

Procedure:
While stirring under nitrogen, 8.8 g (33 mmol) of ethyl bis(3-fluorophenyl)phosphinite are slowly added dropwise to a solution of 7.27 g (16.6 mmol) of 2,2'-bis(bromo-methyl)-1,1'-binaphthyl in 40 ml of o-xylene, which solution has been heated to 120° C., with ethyl bromide distilling off. After the end of the addition, the mixture is heated under reflux for a further two hours and is then cooled to 0° C. The solid is filtered off, washed with cold o-xylene and dried in vacuo. This gives 11.5 g (91 %) of colorless crystals having a melting point of 280°-284° C.
Reaction SMILES: Br[C:2]1[C:3]([OH:21])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Br-].[CH2:23]([Zn+])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH2:23]([C:2]1[C:3]([OH:21])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(O)n2)CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1nc(N2CCNCC2)ncc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of tert-butyl 4-(5-bromo-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (20 g, 56 mmol) and Pd(Amphos)Cl2 (4.0 g 5.6 mmol) in THF (200 mL, dry) was added benzylzinc(II) bromide (168 mL, 168 mmol) under argon and the mixture was stirred at 60° C. overnight. The reaction mixture was diluted with ethyl acetate (1.5 L), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:1 to 100% ethyl acetate) to give 5-benzyl-2-(piperazin-1-yl)pyrimidin-4-ol (8.2 g, 54%) as a pale yellow solid. MS (ES+) C15H18N4O requires: 270, found: 271 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([NH:30][CH3:31])[CH3:29]>>[CH2:28]([N:30]([CH3:31])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:29]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C20H24N6O2, 380.2.