Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:7])[S:5][CH3:6])#[N:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.N1CCCC1>>[NH2:2][C:1]1[C:17]2[CH2:16][CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])[CH2:20][CH2:19][C:18]=2[N:7]=[C:4]([S:5][CH3:6])[N:3]=1
Reactant: O=C1CCC(c2ccccc2Cl)CC1
Reactant: CSC(=N)NC#N
Solvent: C1CCNC1
Product: CSc1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Temperature: 150 °C

Procedure:
A suspension of 1.2 grams of (0.010 mole) of N-cyano-S-methylisothiourea [prepared in the manner disclosed by R. W. Turner; Synthesis, 332 (1975)], 2.1 grams (0.010 mole) of 4-(2-chlorophenyl)cyclohexanone and 0.4 gram (0.005 mole) of pyrrolidine is placed in a glass tube, which is then sealed. The sealed tube is heated at 150° C. for about seven hours. After this time, the sealed tube is cooled in an ice-bath and opened. The reaction mixture is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography using silica gel, yielding 4-amino-2-methylthio-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(Nc2nc3cccc(-c4ccc(S(C)(=O)=O)cc4)n3n2)cc1
Yield: 10.8 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (115 mg, 0.40 mmol) and p-bromoanisole (82 mg, 0.44 mmol) in a manner analogous to Example 77 to yield [5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine (17 mg, 11%) as a yellow powder following purification on a 12 g Isco silica gel column using methanol in dichloromethane (0-10%) as eluent. MP=229° C. (dec.). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.43 (s, 1H), 8.32 (d, J=7.50 Hz, 2H), 8.14 (d, J=7.50 Hz, 2H), 7.54-7.71 (m, 4H), 7.27 (d, J=6.4 Hz, 1H), 6.87 (d, J=7.5 Hz, 2H), 3.71 (s, 3H), 3.34 (s, 3H). MS=395 (MH)+.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[N:5][N:4]=[C:3]1[SH:10].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[C:21]2[N:25]([C:26]=1[C:27](O)=O)[CH:24]=[CH:23][O:22]2.O=P(Cl)(Cl)Cl>C(Cl)Cl>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[C:21]2[N:25]([C:26]=1[C:27]1[S:10][C:3]3=[N:4][N:5]=[C:6]([CH:7]([CH3:9])[CH3:8])[N:2]3[N:1]=1)[CH:24]=[CH:23][O:22]2
Reactant: CC(C)c1nnc(S)n1N
Reactant: O=C(O)c1c(-c2ccc(F)cc2F)nc2occn12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1nnc2sc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 0 °C
Yield: 15 %

Procedure:
A 5 mL round-bottomed flask equipped with a reflux condenser outfitted with a nitrogen inlet adapter was charged with 4-amino-5-isopropyl-4H-1,2,4-triazole-3-thiol (0.15 g, 0.95 mmol, Enamine) and 6-(2,4-difluorophenyl)imidazo[2,1-b]oxazole-5-carboxylic acid (0.25 g, 0.95 mmol) in POCl3 (3.5 mL, 38 mmol) to give a tan suspension. The reaction mixture was heated at about reflux for about 18 h, allowed to cool, and then poured over stirring ice water. The mixture was diluted with DCM and the layers were separated. The organic layer was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to provide a white solid (0.055 g) which was dissolved in a minimal amount of hot ACN and left to cool to ambient temperature for about 2 h. The resulting crystals were isolated by filtration, washed with ACN, and dried under vacuum to give the title compound (0.020 g, 5%): LC/MS (Table 1, Method b) Rt=1.95 min; MS m/z: 387.2 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:9]([CH3:22])[CH:8]=1>C1COCC1.O>[C:18]([O:17][C:15](/[CH:14]=[CH:13]/[C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:23])=[O:5])=[CH:8][C:9]=1[CH3:22])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
Lithium hydroxide monohydrate (384 mg, 9.2 mmol) was added to a solution of 4-((E)-2-tert-butoxycarbonyl-vinyl)-3-methyl-benzoic acid methyl ester from Example E30.1 (1.27 g, 4.6 mmol) in THF (50 ml) and water (20 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with 1M KHSO4, water then brine, dried and concentrated in vacuo to yield the title compound (1.1 g, 92%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:4][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC1CCC(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
1,4-Diaminocyclohexane (cis, trans mixture) (24.0 g, 210 mmol) and triethylamine (16.3 ml, 117 mmol) were dissolved in methylene chloride (400 ml). A solution of triphenylmethyl chloride (32.5 g, 117 mmol) dissolved in methylene chloride (100 ml) was dropwise added under ice-cooling and the mixture was stirred for 15 minutes and at room temperature for 45 minutes. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure. Water (100 ml) was added to the residue and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform/n-hexane=5/1-10/1) to give 18.4 g of 1-amino-4-(triphenylmethylamino)cyclohexane as a pale-yellow oil (25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18]([OH:20])=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH:25](I)(C)[CH3:26]>>[CH2:25]([O:19][C:18](=[O:20])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH3:26]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)O)c(C)c1C
Reactant: CC(C)I
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid and isopropyl iodide is converted to
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].[OH-].[Na+]>CC1C=CC=C(CC2C=CC=CC=2)C=1CC1C=CC=CC=1>[CH3:8][C@H:7]1[CH2:9][C@@H:10]([OH:11])[C@H:4]([C:2]([CH3:3])=[CH2:1])[CH2:5][CH2:6]1
Reactant: CC(C)=CCCC(C)CC=O
Agent: Cc1cccc(Cc2ccccc2)c1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The aluminium siloxide (Ia) or (Ib) was prepared analogously to Example 4 in 5 ml Marlotherm S® (isomer mixture of isomeric dibenzyltoluenes). 200 mmol citronellal were then added at room temperature to a solution containing 2 mmol of freshly prepared aluminium siloxide over a period of 15 min. When the metering in had ended, the reaction mixture was stirred at room temperature for a further 2 h and the reaction was then interrupted by addition of 50 ml 15% strength sodium hydroxide solution. After washing neutral and distilling off the solvent, the reaction product B2 was obtained as a colourless oil, yield: 14.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>O1CCOCC1>[Br:12][C:13]1[CH:14]=[N:15][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(Nc2ncc(Br)cn2)cc1

Procedure:
2-(4-Aminophenyl)acetic acid (4.56 mmol), 5-bromo-2-chloropyrimidine 4 (3.26 mmol), and p-TSA (0.842 mmol) are heated at reflux in 1,4-dioxane (10 mL) and DMSO (2 mL) for 16 h. The mixture is poured onto water and extracted with EtOAc. Concentration of the organic phase gives 2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)acetic acid 22 as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 9.84 (s, 1H), 8.58 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.50 (s, 2H). MS (m/z) (M+1)+: 308.0, 310.0.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=O)=[CH:4][CH:3]=1.NC1C=[C:16](C=CC=1)[C:17]([O:19]CC)=[O:18]>>[O:19]1[C:11]2[CH:12]=[CH:2][CH:3]=[CH:4][C:5]=2[CH:6]=[CH:16][C:17]1=[O:18]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1cccc(N)c1
Product: O=c1ccc2ccccc2o1

Procedure:
The same procedures as Example 1 were carried out except that 150 parts of ethyl p-aminobenzoate were replaced by 150 parts of ethyl m-aminobenzoate. The 2H-1-benzopyran-2-on compound thus obtained was 228 parts.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C(NCC1CCNCC1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)CN1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of benzyl piperidin-4-ylmethylcarbamate (Tetrahedron Lett. 1990, 31, 6903, 6.9 g, 27.8 mmol) in N,N-dimethylformamide (60 mL) were added triethylamine (9.7 mL, 69.5 mmol) and 1-bromo-3,3-dimethylbutan-2-one (7.9 g, 41.7 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and quenched with water (60 mL) followed by extraction with ethyl acetate-toluene mixture (3×30 mL). Concentration and purification by column chromatography on silica gel eluting with ethyl acetate/hexane (2:1) gave the title compound (9.6 g, 100%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH2:19][CH3:20].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[NH:7][C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][C:10]=2[CH2:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N
Reactant: O=C1CCCC1
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1NC1CCCC1

Procedure:
The title compound, white solid, MS: m/e=369.2 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-Amino-cyclopentyl)-2-ethyl-4-trifluoromethyl-benzamide (intermediate S) and cyclopentanone.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:8]=1
Reactant: OCc1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cnc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
4-Hydroxymethylimidazole hydrochloride (10 g) was suspended in dichloromethane (200 ml). ρ-Toluenesulfonyl chloride (15.58 g) was added and triethylamine (25.8 ml) was added dropwise to the stirred reaction mixture which was allowed to stir at room temperature overnight. The mixture was washed with water (2×100 ml) and brine (1×100 ml) and the organic layer was dried and evaporated to leave a clear oil which was recrystallised from ethyl acetate/hexane to afford the title compound as a white crystalline solid (15 g, 80%). 1H NMR (360 MHz, CDCl3) δ2.44 (3H, s), 4.55 (2H, s), 7.21 (1H, s), 7.35 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz 7.98 (1H, s). MS (CI+) m/z 253 (M+H, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CC(C)([O-])C.[K+].Cl[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=1>C(O)(C)(C)C>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)=[CH:28][N:27]=1)[CH3:31]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOc1ccc(CCl)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.58 g, 3.0 mmol, Aldrich, Cat. 525057) in tert-butyl alcohol (5.0 mL) was added a solution of potassium tert-butoxide in tert-butyl alcohol (5.0 mL, 5.0 mmol, 1.00 M, Aldrich Cat. 331341). The reaction mixture was stirred at r.t. for 10 minutes followed by an addition of 5-(chloromethyl)-2-ethoxypyridine (0.54062 g, 3.15 mmol). The reaction mixture was stirred at 65° C. overnight. The reaction mixture was cooled to r.t., quenched with aqueous ammonium chloride, and extracted with EtOAc. The combined organic layers were washed with water and brine successively, dried with MgSO4, and concentrated. The residue was purified by flash chromatograph on a silica gel column using 20% ethyl acetate in methylene chloride as eluent to afford the desired compound. LCMS (M+H)+: m/z=330.4.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:28]([C@@H:25]2[CH2:26][CH2:27][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CCN(Cc3ccccc3)CC2)C1

Procedure:
4.99 g (21.5 mmol) of benzylbis(2-chloroethyl)amine hydrochloride (XX) were dissolved in ethanol (120 ml) and, while stirring, 4.00 g (21.5 mmol) of (R)-(+)-N-Boc-3-aminopyrrolidine and 7.22 g (85.9 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 4.48 g (60%) of yellow solid
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:14]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CS(C)=O.C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH3:3])=[CH:14][CH:15]=1)=[O:27])[CH3:34]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(C(=O)Cc2ccccn2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1)c1ccccn1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of sodium hydride (0.092 g, 3.8 mmoL) in 10 mL of DMSO was stirred under N2 as the product from step 3 (1.0 g, 3.8 mmol) in 5.0 mL of DMSO was added dropwise. After the reaction was stirred for 30 min, a solution of ethyl bromoacetate (0.64 g, 8.83 mmol) in 6.0 mL of toluene was added dropwise, and the reaction was stirred at rt for 1 h. The reaction was then quenched with NH4Cl solution and the solvent was evaporated. The residue was extracted with CH2Cl2 (3×20 mL), combined, washed with saturated NaHCO3, saturated NaCl then dried over Na2SO4. The crude product was purified by flash chromatography using 10% MeOH in CH2Cl2 to give the product (0.65 g, 52%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=2[CH3:27])=[CH:32][CH:31]=1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(Oc2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 26.6 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.41 g), 4-methoxyphenol (0.13 g), 8 M potassium hydroxide solution (0.13 mL) and dimethyl sulfoxide (5 mL) was stirred at 150° C. for 12 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 purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.12 g, 28%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].[O-]Cl.[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1C
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-butyryl-4-(2-methylphenylamino)-8-(3-methylthiopropoxy)quinoline (0.33 g, 0.8 mmol) was dissolved in methylene chloride (15 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride: methanol 95:5 as the eluent gave 0.18 g (53%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Nc1cccc(B(O)O)c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(N)c3)ccn2c1=O
Yield: 39.6 %

Procedure:
Methyl 8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (195 mg, 0.66 mmol) and (3-aminophenyl)-boronic acid (119 mg, 0.87 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (91 mg, 39%).
Reaction SMILES: C(N)(=O)C.C=O.O.[C:8]([OH:11])(=[O:10])[CH3:9].N(CC(O)=O)CC(O)=O.[C:21]([NH:24][CH2:25][C:26]([OH:28])=[O:27])(=[O:23])[CH3:22]>COCCOC>[C:21]([N:24]([CH2:25][C:26]([OH:28])=[O:27])[CH2:9][C:8]([OH:11])=[O:10])(=[O:23])[CH3:22]
Reactant: CC(=O)NCC(=O)O
Reactant: CC(=O)O
Agent: C=O
Agent: CC(N)=O
Agent: O=C(O)CNCC(=O)O
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 125 °C
Yield: 93 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII)(11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (6.5 g, 0.36 mole), acetic acid (16.8 g, 0.28 mol, 0.19 g/mL of DME), DME (90 mL) and Co2 (CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 125° C. for 30 min. HPLC analysis of this stream gave a 93% yield of (XVI), 1% (XIV), and 4% (XVIII).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OCC(C)(C)CO2)=[CH:11][C:10]=1[Cl:23])(=[O:3])[CH3:2].[Br:33][C:34]1[CH:39]=[CH:38][C:37](I)=[C:36]([F:41])[CH:35]=1.C(=O)([O-])O.[Na+].O>COCCOC>[C:26]([O:25][CH2:24][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:37]2[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][C:36]=2[F:41])=[CH:11][C:10]=1[Cl:23])(=[O:28])[CH3:27]
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(=O)NC(CCc1ccc(B2OCC(C)(C)CO2)cc1Cl)(COC(C)=O)COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)NC(CCc1ccc(-c2ccc(Br)cc2F)cc1Cl)(COC(C)=O)COC(C)=O
Reaction time: 24 h
Yield: 56.1 %

Procedure:
A mixed solution of N-{1,1-bis(acetoxymethyl)-3-[2-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]propyl}acetamide (2.05 g) of Reference Example 22, 1-bromo-3-fluoro-4-iodobenzene (1.39 g), sodium hydrogen carbonate (2.02 g) and tetrakistriphenylphosphine palladium (51 mg) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100° C. for 9 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Pyridine (20 mL) and acetic anhydride (2 mL) were added to the residue, and the mixture was stood at room temperature for one day. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.30 g) as white crystals.