Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1.[H-].[Na+]>CN(C)C=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A solution of 2.01 g (10 mmol) of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate in 20 ml of dimethylformamide is admixed with 7 g (40 mmol) of 1-bromo-4-fluorobenzene and 2.5 g (50 mmol) of sodium hydride at 50% in mineral oil. The mixture is stirred at 100° C. for 3 hours and then evaporated to dryness. The residue is taken up in 50 ml of ice-water and extracted with dichloromethane. The organic extracts are evaporated to dryness, to give 3.5 g of an oily product, which is used as it is in the following step.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.CNC1CCCCC1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.[Cu]I.O1CCOCC1>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([N:19]1[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15][C:14]1=[O:13])[CH:11]=[CH:10]2
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Br)ccc3c2)C(=O)C1
Temperature: 150 °C

Procedure:
To a microwave tube charged with a stir bar was added 2,6-dibromonaphthalene (710 mg, 2.5 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (250 mg, 1.2 mmol), copper(I) iodide (48 mg, 0.25 mmol), N,N′-dimethylcyclohexane-1,2-diamine (71 mg, 0.50 mmol), K3PO4 (530 mg, 2.5 mmol), and dioxane (10 mL). The mixture was heated to 150° C. in a microwave reactor for 1 hour. The reaction was diluted with EtOAc, adsorbed onto silica gel, and purified by MPLC (silica gel, EtOAc-Hexanes) to afford the title compound. LC-MS (IE, m/z): 407 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][CH:14]([CH2:18][CH2:19]Cl)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[C:7]([C:6]1[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][O:3][C:2]=1[N:1]1[CH2:19][CH2:18][CH:14]([CH3:13])[C:15]1=[O:16])#[N:8]
Reactant: CC(C)(C)c1coc(N)c1C#N
Reactant: CC(CCCl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC1CCN(c2occ(C(C)(C)C)c2C#N)C1=O
Yield: 21.7 %

Procedure:
To 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)furan and 4.3 g of 2-methyl-4-chlorobutyryl chloride was added 150 ml of toluene. The reaction mixture was allowed to reflux for about 72 hours. The mixture was washed once with 1N hydrochloric acid, once with 2N sodium hydroxide and finally with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed over silica gel while eluting with an 80/20 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 1.3 g of N-[3-cyano-4-(1,1-dimethylethyl)-2-furyl]-3-methyl-2-pyrrolidinone. mp=88°-90° C. Yield 21%.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:31]([CH3:32])=[CH:30][C:13]([CH2:14][NH:15][C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:29])([CH3:28])[C@H:22]34)=[O:17])=[CH:12][C:11]=2[CH3:33])[CH2:4][O:3]1>C(O)(=O)C.O>[OH:7][CH2:6][CH:5]([CH2:4][OH:3])[CH2:8][O:9][C:10]1[C:11]([CH3:33])=[CH:12][C:13]([CH2:14][NH:15][C:16]([C:18]2[S:25][C:24]([CH3:26])=[C:23]3[C:19]=2[CH2:20][C@H:21]2[C:27]([CH3:29])([CH3:28])[C@H:22]23)=[O:17])=[CH:30][C:31]=1[CH3:32]
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1COC(C)(C)OC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(CO)CO
Yield: 85.5 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-benzylamide (28 mg, 0.058 mmol) in acetic acid (1.6 mL) and water (0.4 mL) is stirred at rt for 1 h before it is separated by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-2-hydroxymethyl-propoxy)-3,5-dimethyl-benzylamide (22 mg) as a colourless solid. LC-MS: tR=0.96 min, [M+1]+=444.30; 1H NMR (CDCl3): δ 6.95 (s, 2H), 5.77 (t br, J=5.8 Hz, 1H), 4.51-4.37 (m, 2H), 4.00 (d, J=5.3 Hz, 4H), 3.90 (d, J=5.3 Hz, 2H), 2.93 (dd, J=5.9, 17.6 Hz, 1H) 2.73 (d, J=17.6 Hz, 1H), 2.36 (s, 3H), 2.33-2.20 (m, 9H), 1.93-1.86 (m, 2H), 1.12 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7][CH:6]=1)[CH3:2].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.[O-]CC.[Na+]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:22]([NH2:21])=[S:23])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(N)=S)nc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
A mixture of ethyl-6-amino-nicotinate (2.5 g, 15 mmol) and benzoyl isothiocyanate (2.45 g, 15 mmol) in THF (20 mL) was heated at 40° C. for 4 h. To this mixture at RT, was added sodium ethoxide (2.04 g, 30 mmol) in ethanol (10 mL). After stirring the resulting mixture at RT for 16 h, the volatiles were removed in vacuo. The residue was suspended in aqueous NH4Cl and the solid formed was collected by filtration, rinsed with water and dried to afford 6-thioureido-nicotinic acid ethyl ester as a white solid (2.6 g, 77% yield). LC/MS; (M+H)+=226.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]=[C:26]=[S:27])[CH3:24]>>[CH2:23]([NH:25][C:26](=[S:27])[NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[O:17])[CH3:24]
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCN=C=S
Product: CCNC(=S)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 17 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carboxamide and ethyl isothiocyanate. The analytical values are summarized in Table I.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.O>[C:20]([C:24]1[CH:48]=[CH:47][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[NH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:32]=2[CH3:46])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cn1cc(Br)cc(Nc2cc(C(C)(C)C)[nH]n2)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2cc(C(C)(C)C)[nH]n2)c(=O)n(C)c1
Temperature: 135 °C
Yield: 105.4 %

Procedure:
A mixture of 5-Bromo-3-(5-tert-butyl-1H-pyrazol-3-ylamino)-1-methyl-1H-pyridin-2-one (125 mg; 0.38 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (180 mg; 0.46 mmol), tetrakis-(triphenylphosphine)palladium (24 mg; 0.02 mmol), sodium carbonate (400 mg; 1.2 mmol), and 1,2-dimethoxyethane (4 mL) and water (4 mL) were heated in a sealed microwave reactor for 5 min (135° C., 300 W). The mixture diluted with ethyl acetate, adsorbed onto silica gel, and flash chromatographed (9:1 CH2Cl2:MeOH) to give 4-tert-Butyl-N-{3-[5-(5-tert-butyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-benzamide as a tan solid (205 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-])=O)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5]>[Fe]>[Br:18][C:15]1[CH:14]=[C:13]2[C:12]([C:4]([CH3:5])([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3](=[O:2])[NH:19]2)=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Product: CC1(c2ccccc2)C(=O)Nc2cc(Br)ccc21
Yield: 59.1 %

Procedure:
Following similar methods to those described in Preparation 326 starting from 2-(4-bromo-2-nitro-phenyl)-2-phenyl-propionic acid methyl ester (1.3 g, 4.9 mmol) and iron powder (890 mg, 15 mmol) gave the title compound (875 mg) as a yellow solid. MS: [M+H]+=302.
Reaction SMILES: C(S([C:8]1[N:13]=[C:12]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:23]([NH2:25])=[O:24])=[CH:15]2)[CH:11]=[CH:10][N:9]=1)(=O)=O)CCC.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30])[CH3:27]>O1CCOCC1>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:8]2[N:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([C:23](=[O:24])[NH2:25])=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: CCCCS(=O)(=O)c1nccc(-n2cc(C(N)=O)c3ccccc32)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3cc(C(N)=O)c4ccccc43)n2)CC1
Yield: 83.3 %

Procedure:
1-(2-Butylsulfonyl-pyrimidin-4-yl)-1H-indole-3-carboxylic acid amide (1.5568 g, 4.349 mmol) was dissolved in dry dioxane (150 mL), and 4-amino-cyclohexanecarboxylic acid ethyl ester (1.86 g, 10.87 mmol) was added. The mixture was heated at reflux overnight, then evaporated to dryness, poured into water, extracted into EtOAc, and dried under vacuum. The product was recrystallized from EtOH-free CHCl3 to provide 4-[4-(3-carbamoyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (1.477 g, 83% yield) as a white solid (Compound 322).
Reaction SMILES: ClC1C=CC(C2N=C(N3CC(NCC)(C(N)=O)C3)N3C(=O)NN=C3C=2C2C=CC(Cl)=CC=2)=CC=1.IC.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:49]=[C:48]([N:50]3[CH2:53][C:52]([NH:57][CH2:58][CH3:59])([C:54]([NH2:56])=[O:55])[CH2:51]3)[N:47]3[C:60](=[O:65])[N:61]([CH2:63]C)[N:62]=[C:46]3[C:45]=2[C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[N:49]=[C:48]([N:50]3[CH2:53][C:52]([NH:57][CH2:58][CH3:59])([C:54]([NH2:56])=[O:55])[CH2:51]3)[N:47]3[C:60](=[O:65])[N:61]([CH3:63])[N:62]=[C:46]3[C:45]=2[C:66]2[CH:67]=[CH:68][C:69]([Cl:72])=[CH:70][CH:71]=2)=[CH:42][CH:43]=1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Agent: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3n[nH]c(=O)n23)C1
Solvent: CI
Product: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(C)c(=O)n23)C1

Procedure:
The title compound was prepared by coupling 1-(7,8-bis(4-chlorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide with iodomethane in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time 3.318 min, [M+H]30 =512.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:34]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Cc1ccc(C2CNCCN2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccc(C2CN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C)CCN2)cc1
Temperature: 115 °C
Yield: 29.9 %

Procedure:
A suspension of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.84 g) in pyridine (20 cc), (RS)-2-(4-methylphenyl)piperazine (5.83 g) and triethylamine (1.24 g) is heated to a temperature in the region of 115° C. for 37 hours. After cooling to approximately 20° C., the insoluble matter is drained and washed with ethanol (2×5 cc) and ethyl ether (2×5 cc). After recrystallization in dimethylformamide (25 cc), (RS)-7-fluoro-1-methyl-8-[3-(4-methylphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.8 g) is obtained in the form of a yellow solid, decomposing at 282° C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10](I)=[CH:9][C:8]=1[O:16][CH:17]([CH3:19])[CH3:18].[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[C:21]=[O:22]>C1COCC1>[Cl:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:21]([NH:20][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[O:22])=[CH:9][C:8]=1[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: COc1cc(I)cc(OC(C)C)c1Cl
Reactant: COC(=O)c1ccc(N=C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c(Cl)c(OC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.4 %

Procedure:
n-Butyllithium (364 μl, 0.909 mmol) was slowly added to a solution of 2-chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3) (270 mg, 0.827 mmol) in anhydrous THF (5 mL) at −78° C. After stirring for 15 min at this temperature a solution of methyl 4-isocyanatobenzoate (176 mg, 0.992 mmol) in anhydrous THF (5 mL) was added dropwise. The solution was allowed to warm to RT and stirred for a further 20 h. The reaction mixture was partitioned between DCM (40 mL) and brine (100 mL). The phases were separated and the organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40 g, 0-40% EtOAc in isohexane) to afford methyl 4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5) (20 mg, 6%) as a colourless oil: m/z 376 [M−H]− (ES−).
Reaction SMILES: [O-:1]S([O-])(=O)=O.[Na+].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=1)=[O:23])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[N:26][C:27]([S:30]([CH3:31])=[O:1])=[N:28][CH:29]=1)=[O:23])[CH3:20]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCOC(=O)c1cnc(SC)nc1-c1ccccc1F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cnc(S(C)=O)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A Na2SO4-dried solution of m-CPBA (10.64 g, ca. 45 mmol) in CH2Cl2 (100 mL) was added drop wise to a cold (−65° C.) solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester in CH2Cl2 (200 mL) keeping the temperature below −65° C. The yellow suspension was allowed to warm to 0° C. over 1 hour. After 3 hours at 0° C., a saturated aqueous NaHCO3 solution (100 mL) was added to quench the reaction. The organic layer was separated, washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The product was taken up in CH2Cl2 and washed again with a saturated aqueous NaHCO3 solution to remove traces of m-C(P)BA giving 4-(2-fluoro-phenyl)-2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester (12.86 g, >100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](OCC)([O:18]CC)[C:13](OCC)=O)[CH3:10]>>[CH2:9]([O:11][C:12]([C:13]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)=[O:18])[CH3:10]
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Reactant: Nc1ccccc1O
Product: CCOC(=O)c1nc2ccccc2o1
Temperature: 110 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To 2-aminophenol (437 mg, 4 mmol) was added ethyl triethoxyacetate (3.5 g, 4 eq). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 516 mg of benzoxazole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[C:13]([O:15][CH2:16][CH3:17])(=[O:14])/[CH:12]=[CH:11]/[C:10]#[CH:9]
Reactant: CCOC(=O)/C=C/C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#C/C=C/C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Potassium carbonate (563 mg, 4.07 mmol) was added to a solution of ethyl 5-trimethylsilyl-(E)-2-penten-4-ynoate(800 mg, 4.07 mmol) in ethanol (10 ml), and the mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography to give ethyl (E)-2-penten-4-ynoate (79%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:18](=[O:21])[NH:19][CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C@@H:9]([NH:7][CH3:6])[C:18]([NH:19][CH3:20])=[O:21]
Reactant: CNC(=O)[C@@H](Cc1ccccc1F)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1F)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamic acid tert-butylester (2.4 g; 7.73 mmol) was dissolved in methylene chloride. Trifluoroacetic acid (10 mL) was added and the reaction mixture was stirred for 30 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 1.1 g of (2R)-3-(2-fluorophenyl)-N-methyl-2-(methylamino)- propionamide.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6].Cl>>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc(-c2ncc(C(=O)[O-])cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(-c2ncc(C(=O)O)cn2)cc1

Procedure:
NaOH aqueous solution was added to ethyl-2-(4-butyloxyphenyl)-5-pyrimidinecarboxylate (VI), followed by heating the mixture, adding hydrochloric acid, filtering off the resulting precipitates, and drying to obtain 2-(4-butyloxyphenyl)-5-pyrimidinecarboxylic acid (VII). This compound (VII) (1.0 g, 3.7 mmols), 4-dimethylaminopyridine (0.2 g), N,N'-dicyclohexylcarbodiimide (1.7 g) and 3-chloro-4-fluorophenol (0.7 g) were dissolved in dichloromethane (30 ml), followed by agitating the solution for 5 minutes, further agitating at room temperature overnight, filtering off the resulting precipitates, washing the dichloromethane phase with 2N-hydrochloric acid, then with 2N-NaOH aqueous solution and further with water till the washing water became pH 7, drying over magnesium sulfate, concentrating under reduced pressure, and recrystallizing the residual white solids from methanol to obtain the objective 3-chloro-4-fluorophenyl-2-(4-butyloxyphenyl)5-pyrimidinecarboxylate (0.5 g). This compound had a crystalline-smectic point (C-S point) of 152.3° C. and a smectic-clearing point (S-I point) of 165.4° C. The elemental analysis values of this compound were as follows: C:62.9%, H: 4.5%, N: 7.0% (calculated values in terms of C21H18ClFN2O3 --c: 62.92%, H:4.53%, N: 6.99%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]([S:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][N:11]=2)=[N:6][N:5]=[N:4]1.[BH4-].[Na+].Cl>CO>[ClH:1].[CH3:2][N:3]1[C:7]([S:8][CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[N:6][N:5]=[N:4]1
Reactant: Cn1nnnc1SCC1=NCCc2cc(O)c(O)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnnc1SCC1NCCc2cc(O)c(O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.5 %

Procedure:
1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-3,4-dihydroisoquinoline hydrochloride (0.2 g) was dissolved in methanol (5 ml) under warming. To the solution was added sodium borohydride (50 mg) and the mixture was stirred for 1.5 hours at room temperature. 10% Hydrochloric acid was added to the reaction mixture and the solution was concentrated. Dried methanol was added to the residue and the insoluble material was filtered off, after which the filtrate was evaporated. The residue was crystallized by treating with acetone to give 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.16 g), mp 215° to 216° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(CBr)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a suspension of methyl 4-chloro-3-methylbenzoate I (19.9 g, 108 mmol) and N-bromosuccinimide (NBS, 20.2 g, 114 mmol) in carbon tetrachloride (500 mL) was added benzoyl peroxide (1.30 g, 5.4 mmol), and the mixture was stirred at 90° C. overnight. The mixture was then cooled and the white precipitate was removed by filtration. The filtrate was concentrated and the resulting solid was re-crystallized from ethyl acetate to give methyl 3-bromomethy-4-chlorobenzoate II (15.0 g, 57 mmol, 53%) as a white solid: 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.63 (s, 2H) 7.49 (d, J=8.3 Hz, 1H), 7.94 (dd, J=2.1, 8.3 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Product: COc1cc2c(cc1C)C(C(C)(C)C)=CCC2(C)C
Yield: 9.7 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 30, 2.0 g, 9.2 mmol) was reacted with a solution of 2M tert-butylmagnesiumchloride (46 mL, 92.0 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.23 g (10%) of the title product as a yellow oil.