Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2].[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=1)[CH2:21][NH2:22]>>[C:1]([CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH2:30][OH:31])[CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)[CH3:7])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: CCOC(=O)C(C)Oc1ccc(CC(C)=O)cc1
Product: CCOC(=O)C(C)Oc1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1

Procedure:
The compound was prepared as in Example 1 from 1-(4-(1-carboethoxy)ethoxyphenyl) propan-2-one (1.22 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (0.95 g), and crystallised from benzene m.p. 53°-55° as a 53:47 mixture of diastereoisomers.
Reaction SMILES: [N:1]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[CH2:9][CH2:8][C:7](=[CH2:10])[CH2:6][CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[C:17]([C:13]1[CH:12]=[C:11]([C:4]2([NH2:1])[CH2:5][CH2:6][C:7](=[CH2:10])[CH2:8][CH2:9]2)[CH:16]=[CH:15][CH:14]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C=C1CCC(N=[N+]=[N-])(c2cccc(C(C)(C)C)c2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: C=C1CCC(N)(c2cccc(C(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(1-azido-4-methylene-cyclohexyl)-3-tert-butyl-benzene (820 mg, 3.04 mmol) in diethyl ether (10 mL) was added to a heterogeneous mixture of lithium aluminum hydride (510 mg, 13.4 mmol) in diethyl ether (10 mL) and was placed into a preheated oil bath at 40° C. After heating at reflux for 24 h, the solution was cooled to ambient temperature, and celite and sodium sulfate decahydrate was added. After stirring for 1 h, the heterogeneous mixture was filtered through celite to yield 1-(3-tert-butyl-phenyl)-4-methylene-cyclohexylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:68][CH2:69][CH2:70][CH2:71][CH:72]2[CH2:76][CH2:75][NH:74][CH2:73]2)[CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]1[CH2:75][CH2:76][CH:72]([CH2:71][CH2:70][CH2:69][CH2:68][N:63]3[CH2:64][CH2:65][CH2:66][CH2:67]3)[CH2:73]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: C(CCN1CCCC1)CC1CCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(CCCCN4CCCC4)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-[4-(pyrrolidin-1-yl)-butyl]-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[N:4][C:5]([CH3:14])=[C:6]([C:12]=1[OH:13])[C:7]([O:9]CC)=[O:8].O.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[C:3]([Cl:15])=[N:4][C:5]([CH3:14])=[C:6]([C:12]=1[OH:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(C)nc(Cl)c(Cl)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(Cl)c(Cl)c(O)c1C(=O)O

Procedure:
36 g (0.14 mol) of ethyl 5,6-dichloro-4-hydroxy-2-methyl-nicotinate are boiled under reflux in 88 ml of ethanol and 175 ml of water with 24.2 g (0.43 mol) of potassium hydroxide for thirty minutes. The cooled mixture is brought to a pH of 1 with half-concentrated hydrochloric acid, while cooling with ice. The product which precipitates is isolated, washed with water and dried.
Reaction SMILES: [CH:1]1([CH:6]([OH:8])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][C:21]=2[N:22]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH:6]([O:8][C:12]2[CH:13]=[CH:14][C:15]3[CH2:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][C:21]=3[N:22]=2)[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC(O)C1CCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C1CCCC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 1-cyclopentylethanol (0.22 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 100° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-(1-cyclopentylethoxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.45 g, 70%) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH:36]([C:33]1[CH:32]=[CH:31][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)[CH:25]=2)=[CH:35][CH:34]=1)=[O:37]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(C=O)cc4)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccc(C=O)cc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-(4-{2-[2-(4′-formylbiphenyl-3-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.711 mmol) in ethanol (8.9 mL) was treated with NaOH (aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield a white, crystalline solid: Rf=0.14 in 6:4 ethyl acetate:hexanes; MS (EI) 486.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)CC[CH2:4][CH2:3][CH2:2]1.C(=O)CC(C)C.C(N)CCC.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:1]([N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Solvent: CCCCN
Product: CCCCN(CCC(C)C)C(=O)Nc1ncc(SCC(=O)O)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, butylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:20][C:21]1[CH:26]=[C:25](I)[C:24]([F:28])=[CH:23][N:22]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[C:25]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]3)[C:24]([F:28])=[CH:23][N:22]=1
Reactant: Fc1cnc(Cl)cc1I
Reactant: CN1CCc2cccc(N)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCc2cccc(Nc3cc(Cl)ncc3F)c2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (1.369 g, 7.77 mmol), cesium carbonate (5.06 g, 15.54 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.270 g, 0.47 mmol), palladium(II) acetate (0.070 g, 0.31 mmol) were added in order to a mixture of 2-chloro-5-fluoro-4-iodopyridine (2.000 g, 7.77 mmol) in dioxane (150 mL) at 20° C. under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 4 hours and then left to stand at room temperature overnight. The mixture was filtered through Celite and the residue washed with CH2Cl2 (20 mL). The filtrate was evaporated and the residue dissolved in CH2Cl2 (100 mL) and then washed sequentially with water (2×150 mL) and a saturated solution of NaCl (100 mL). The organic layer was dried over Na2SO4 and then evaporated to leave a solid. The solid was triturated with Et2O and then dried under vacuum to afford 8-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (2.117 g, 89% yield); 1H NMR spectrum (300 MHz, DMSO): δ 2.97 (2H, t), 3.06 (3H, s), 3.57 (2H, t), 6.97 (1H, dd), 7.42 (1H, d), 7.47-7.49 (2H, m), 8.26 (1H, d), 11.66 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =306.39 and 308.36.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23]/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:19][CH2:18]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:43][CH2:44][C:45]([NH2:47])=[O:46]>>[C:8]1([C:6]2[N:7]=[C:2]([NH:43][CH2:44][C:45]([NH2:47])=[O:46])[CH:3]=[C:4]([NH:14][C:15](=[O:32])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23]/[CH:24]=[CH:25]/[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)[N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CN1CCN(C/C=C/c2ccccc2)CC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNc1cc(NC(=O)CN2CCN(C/C=C/c3ccccc3)CC2)nc(-c2ccccc2)n1
Temperature: 100 °C
Yield: 3.9 %

Procedure:
To a crude sample of N-(6-chloro-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide (22.54) (0.75 g in 60 ml DMSO) were added glycinamide hydrochloride (1.85 g in 10 ml DMSO) and N,N-diisopropylethylamine (2.96 ml) and the mixture heated to 100° C. for 16 hrs. The solvent was then removed in vacuo and the residue purified twice by flash chromatography on silica gel using mixtures of dichloromethane and methanol (97:3, 95:5 then 93:7 v/v/v). Further purification by recrystallization from methanol furnished the title compound (32 mg over 2 steps).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][OH:10])=[S:6].[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:16])([Cl:15])[CH:12]([OH:11])[O:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][O:10][CH:12]([OH:11])[C:13]([Cl:16])([Cl:15])[Cl:14])=[S:6]
Reactant: OCCNC(=S)NCCO
Reactant: O=CC(Cl)(Cl)Cl
Product: OC(OCCNC(=S)NCCOC(O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Temperature: 80 °C

Procedure:
To 98.4 g (0.6 mole) of 1,3-bis(2-hydroxyethyl)thiourea as 65° C. was slowly added 182 g (1.24 moles) of chloral while the temperature was maintained below 75° C. by means of external cooling. The reaction mixture was vigorously stirred and heated at 80° C. for 1 hour. On cooling 275 g of a viscous syrupy product was isolated.
Reaction SMILES: O.[ClH:2].[C:3]([N:11]1[CH2:16][CH2:15][O:14][C:13]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=2)([CH2:17][CH2:18]N2CCC(NC(N(C)C)=O)(C3C=CC=CC=3)CC2)[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1CCOC(CCN2CCC(C3C=CC=CC=3)(NC(N(C)C)=O)CC2)(C2C=CC(F)=C(F)C=2)C1)(=O)C1C=CC=CC=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:99][C:100]1[O:101][C:102]([C:105]2([C:111]3[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=3)[CH2:110][CH2:109][NH:108][CH2:107][CH2:106]2)=[N:103][N:104]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:2].[ClH:2].[NH2:99][C:100]1[O:101][C:102]([C:105]2([C:111]3[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=3)[CH2:106][CH2:107][N:108]([CH2:18][CH2:17][C:13]3([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=4)[O:14][CH2:15][CH2:16][N:11]([C:3](=[O:10])[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:12]3)[CH2:109][CH2:110]2)=[N:103][N:104]=1
Reactant: Nc1nnc(C2(c3ccccc3)CCNCC2)o1
Reactant: CN(C)C(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc(C2(c3ccccc3)CCN(CCC3(c4ccc(F)c(F)c4)CN(C(=O)c4ccccc4)CCO3)CC2)o1
Yield: 192.4 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 45 from 1.2 g of the compound obtained in step C of EXAMPLE 37, 1.4 g of 4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidine p-toluenesulfonate, 1.2 g of K2CO3 and 3 ml of DMF to give 0.6 g of the expected product. M.p.=153° C.
Reaction SMILES: [CH3:1][C@@:2]1([O:35]C(=O)C2C=CC=CC=2)[C@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@@H:14]([CH2:25][O:26]C(=O)C2C=CC=CC=2)[O:13][C@H:3]1[O:4]C(=O)C1C=CC=CC=1.[C-]#N.[K+]>CO>[CH3:1][C@@:2]1([OH:35])[C@H:15]([OH:16])[C@@H:14]([CH2:25][OH:26])[O:13][CH:3]1[OH:4]
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: C[C@]1(O)C(O)O[C@H](CO)[C@H]1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 2-C-methyl-1,2,3,5-tetra-O-benzoyl-β-D-ribofuranose 1.3, (50 g) in anhydrous MeOH (1000 mL) was added KCN (150 mg) and the mixture was allowed to stir at room temperature under argon for 15 hr during which time all the material dissolved in the solvent and the solution became clear. The solvent was evaporated and the residue was dried under vacuum to deliver 14.9 g of product 7.2.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (300.0 mg, 0.95 mmol) in DMSO (2 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (227.0 mg, 1.14 mmol), DIEA (367.0 mg, 2.82 mmol). The resulting solution was stirred overnight at 100° C. and then diluted with water (10 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 20%-50% ethyl acetate in petroleum ether to afford methyl 3-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (200 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([N:23]([CH3:24])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CNC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimadazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dimethylamine (2.26 g, 0.050 mole) in tetrahydrofuran (20 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was evaporated to an oil and partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed once with water (50 ml), twice with 5% potassium hydroxide solution (50 ml portions), and once more with water (50 ml). Drying over magnesium sulfate, treatment with charcoal, filtration and evaporation of the solvents gave a residue which upon recrystallization from hot isopropyl ether and drying under high vacuum gave 3.20 g (59%) of title compound, mp 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1Cl
Temperature: 120 °C
Yield: 89 %

Procedure:
To a solution of 3-chloro-4-methylphenol (2.5 g, 17.53 mmol) and 4-fluorobenzaldehyde (2.2 g, 17.73 mmol) in DMF (40 ml), was added K2CO3 (2.91 g, 21.04 mmol). The solution was heated at 120° C. overnight: The reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4 and evaporated in vacuo to afford the title compound (5.5 g, 15.61 mmol, 89% yield). LCMS: rt=3.80 min, [M+H+]=247
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=O)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[C:27]1=O)[CH2:33]2>O.C1COCC1.CCCCCC.[Cl-].[Cl-].[Cl-].[Ti+3].[Zn]>[Si:9]([O:8][C:16]1[CH:17]=[C:18]([CH2:19][O:21][CH:22]=[C:27]2[CH:28]3[CH2:34][CH:32]4[CH2:31][CH:30]([CH2:35][CH:26]2[CH2:33]4)[CH2:29]3)[CH:23]=[CH:24][CH:25]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(COC=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 82.2 %

Procedure:
To a four-necked round-bottom flask equipped with a refluxing condenser and mechanical stirrer was added 1.5 L of dry THF under argon. Titanium trichloride (TiCl3, 200 g, 1.29 mol) was then added to the flask with stirring. After 15 minutes of stirring, powdered zinc (130 g, 2.0 mol) was added in portions and the flask was heated in hot water for 25 minutes. The reaction flask was then cooled in an ice-salt bath and the temperature of the mixture maintained at 5° to 7° C. Triethylamine (2.0 mL) was added to the suspension with caution (the reaction is extremely exothermic). The reaction started in approximately 5 to 10 minutes. After the reaction subsided, an additional amount of triethylamine (200 mL) was added and the mixture heated under reflux for 3 hours. After this period, a solution of methyl 3-tert-butyldimethylsiloxybenzoate (100 g, 0.37 mol) and 2-adamantanone (85.0 g, 0.57 mol) in 400 mL of dry THF was added dropwise to the refluxing mixture over 5 hours. The reaction mixture was then cooled to room temperature and was diluted with hexane (4 L) and the stirring continued. The suspended solids were then allowed to settle and the organic layer decanted. The black solid was washed with diethyl ether (2×1 L). Hexane (1 L) was added to the black material, followed by 1 L of water and the organic layer was removed. The aqueous layer was washed a second time with 1.5 L of hexane. The combined hexane and ether layers were then gravity filtered and the resulting solution was dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography over silica gel with 5% ethyl acetate/hexane gave 117 g (81% yield) of 2 as a clear oil.
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[C:13]3[CH2:20][CH:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:22][CH:11]([C:12]=23)[CH2:10]1)(=O)C1C=CC=CC=1.C([Li])CCC.Cl>C1COCC1.CCCCCC>[C:18]([C:14]1[CH:15]=[CH:16][C:17]2[NH:9][CH2:10][C@@H:11]3[CH2:22][C@H:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:20][C:13]=1[C:12]=23)#[N:19]
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)[C@@H]1Cc2c(C#N)ccc3c2[C@H](CN3)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 113.8 %

Procedure:
To a stirred solution of 4.8 g (0.0124 mol) of 1-benzoyl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole prepared as in Part A hereof in 200 mL of THF cooled to -78° C. under N2 atmosphere, were added 16 mL (0.025 mol) of 1.6 M solution of n-butyl-lithium in hexane. The reaction mixture was stirred at -78° C. for 30 minutes and then allowed to warm to -20° C. To the reaction mixture was added 100 mL of 1 N HCl. The mixture was extracted once with ethyl ether. The acidic solution was made alkaline with the addition of cold 5 N NaOH. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed with saturated aqueous NaCl solution. The CH2Cl2 solution was dried over MgSO4 and evaporated to give 4 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 3 g (85%) of product as an oil, which upon standing solidified.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Br:13])[CH:7]=1)[CH3:2].I[CH2:16][CH3:17]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][CH3:17])=[C:8]([Br:13])[CH:7]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Product: CCOC(=O)Cc1ccc(OCC)c(Br)c1

Procedure:
Prepared according to the procedure described in Example 123, Step 1, using the following starting materials: (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and iodoethane.