Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:43][C@H:44]1[CH2:47][C@@H:46]([C:48]([N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[C:45]1([CH3:56])[CH3:55].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:43][C@H:44]4[CH2:47][C@@H:46]([C:48]([N:50]5[CH2:54][CH2:53][CH2:52][CH2:51]5)=[O:49])[C:45]4([CH3:56])[CH3:55])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.3 g, 0.602 mmol) in DCM (1 ml) a solution of (COCl)2 (0.52 ml, 6.02 mmol) in DCM (4 ml) was added at about 0° C. and the reaction mixture was allowed to stir at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a stirred solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(pyrrolidin-1-yl)methanone (Intermediate 13, 0.288 g, 1.023 mmol) in DCM (5 ml) and Et3N (0.16 ml, 1.204 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, 1N HCl, water, brine and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.230 g; Yield: 56.5%; 1H NMR (300 MHz, CDCl3): δ 6.38 (d, 1H, J=8.4 Hz), 4.73 (s, 1H), 4.58 (s, 1H), 4.50-4.42 (m, 1H), 4.13-4.02 (m, 1H), 3.56-3.28 (m, 5H), 3.18-3.07 (m, 1H), 2.79 (t, 1H, J=7.2 Hz), 2.55-2.33 (m, 2H), 2.27-2.18 (m, 1H), 2.04 (s, 3H), 2.00-1.74 (m, 8H), 1.72-1.10 (m, 20H), 0.95, 0.92, 0.88, 0.83 (s, 22H); Mass: [M+Na]+ 714 (100%); IR (KBr, cm−1): 3372, 2943, 2864, 1736, 1730, 1652, 1636, 1623, 1501, 1459, 1444, 1369, 1248, 1192, 1024, 979, 881, 853; M.R: 125.4° C.-135.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(O)c(Cl)c1
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)c(Cl)c3)c2cc1OC
Yield: 71.9 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.144 g of 4-amino-2-chlorophenol, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.256 g of 4-(3-chloro-4-hydroxy-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 230-232° C.; mass spectrum (EI, m/e): M 355.0719.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=1)=[O:12])([O-:3])=[O:2].[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([Br:23])[CH:15]=1)[C:11](=[O:12])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCOc1ccc(NC(=O)Nc2ccccc2[N+](=O)[O-])cc1Br
Product: CCOc1ccc(N(C(=O)CCl)C(=O)Nc2ccccc2[N+](=O)[O-])cc1Br

Procedure:
A solution containing N-(2-Nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea (5.76 g) and chloroacetyl chloride (413 mL) was refluxed under nitrogen for 30 min. After the excess chloroacetyl chloride was removed in vacuo. diethyl ether (50 mL) was added and the resulting solid was filtered and dried to yield N'-(2-chloroacetyl)-N-(2-nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C(COC)OC>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: COCCOC
Product: COCCCOc1ccnc(CCl)c1C
Yield: 114.8 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in dimethoxyethane (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise into the solution in a temperature that did not exceed 25° C. Stirring was carried out at room temperature, and then after it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.25 g (yield: 99.2%)).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17]1([CH3:24])[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:20]2[CH:21]=[CH:22][C:17]([CH3:24])=[CH:18][CH:19]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: Cc1ccc(Cl)cc1
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)C)cc2O)cc1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and p-toluyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]([O:26][CH3:27])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[CH:17]=1)[CH3:11]>ClCCCl>[Cl:5][CH2:6][C:7]([C:20]1[CH:19]=[C:18]([C:16]2[CH:17]=[C:12]([CH2:10][CH3:11])[CH:13]=[CH:14][C:15]=2[O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[OH:24])=[O:8]
Reactant: CCc1ccc(OC)c(-c2ccc(OC)cc2)c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1ccc(OC)c(-c2ccc(O)c(C(=O)CCl)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture was prepared by suspending 25 g of aluminium chloride into 100 ml of 1,2-dichloroethane. The mixture, wherein 5 ml chloroacetyl chloride was added, was stirred for 1 hour at room temperature, followed by dropwise addition of 5-ethyl-2,4'-dimethoxy-biphenyl, wherein 10 g of 1.2-dichloroethane was dropwise and stirred overnight at room temperature. The reaction mixture was transferred into ice water to extract with dichloroethane. The extract was washed with saturated salt water, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column chromatography (10:1, n-hexane:ethyl acetate) and recrystallized from chloroform/n-hexane to yield 2.5 g of light yellow and powdered 2-chloroacetyl-4-(5-ethyl-2-methoxyphenyl)phenol having a m.p. of 67.0°-68.0° C. Then, the fraction which was eluted with n-hexane/ethyl acetate: 3/1, was concentrated. The concentrate was recrystallized from chloroform/n-hexane to yield 1.5 g of white powder 3,3-bischloroacetyl-5-ethyl-2,4'-biphenyldiol having a m.p. of 154.0°-155.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].C(=O)(O)[O-:14].[Na+]>CS(C)=O.C(OCC)C>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:14])[CH2:10][C:11]#[CH:12]
Reactant: C#CCCOCCCCCCBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: C#CCCOCCCCCC=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
6-Bromohexylbut-3-ynyl ether (DE3513885A1) (525 mg) in DMSO (2 ml) was added to a mixture of sodium bicarbonate (1 g) in DMSO (8 ml) at 150° C. with vigorous stirring and nitrogen bubbling through the solution. The mixture was stirred for 20 min at 150° C. and then allowed to cool to room temperature, diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether and the combined ether layers were washed with dilute hydrochloric acid, brine, dried (MgSO4) and evaporated to dryness to give the title compound (325 mg): IR 1726 cm−1 MS(TSP+ve) m/z 186 (M+MH4)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15](Br)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:22])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn]([C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)(CCCC)CCCC)CCC>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:22])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCn1c(Br)nc2c(N)nc(NCCc3ccccc3)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCn1c(-c2ccco2)nc2c(N)nc(NCCc3ccccc3)nc21
Temperature: 60 °C

Procedure:
A mixture of 2-(2-phenylethylamino)-8-bromo-9-ethyl-9H-purin-6-ylamine (0.28 mmol), tributylstannyl furan (440 μL, 1.4 mmol), and bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol) was dissolved in dry tetrahydrofuran (10 mL), and heated at 60° C. for 3 hours. The solvent was removed in vacuo, and the residue was partitioned between water and chloroform. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in CHCl3/MeOH and extracted with chloroform. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on a silica gel column eluting with ethyl acetate/cyclohexane/methanol (60/36/4) to give 2-(2-phenylethylamino)-8-(furan-2-yl)-9-ethyl-9H-purin-6-ylamine as a chromatographically pure solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:26]([N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:27][CH2:26][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:9][CH:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(CN2CCNCC2c2ccccc2)cc(OC)c1OC
Reactant: CCN(CC)CCCl
Product: CCN(CC)CCN1CCN(Cc2cc(OC)c(OC)c(OC)c2)C(c2ccccc2)C1

Procedure:
1-(3',4',5'-Trimethoxy benzyl)-2-phenyl piperazine prepared according to Example 11, is alkylated by means of diethylamino ethylchloride by following the procedure described in Example 2 (c). The resulting reaction product is obtained in the form of yellow oil boiling at 200° C./0.03 mm. Hg.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH:7]=[CH:6]1)(=O)C.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>ClCCl>[C:12]([O:11][C@@H:10]1[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH2:7][CH:6]=[CH:5]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@H]1OCC=C[C@@H]1OC(C)=O

Procedure:
3,4,6-tri-O-acetyl-D-glucal (9.70 g; 35.6 mmol) was reacted at 0° C. with triethylsilane (4.96 g; 42.7 mmol) and borontrifluoride-etherate (3.04 g; 21.4 mmol) in dichloromethane (110 ml) under an atmosphere of argon for 5 minutes. The solution was poured into aqueous NaHCO3 solution and extracted several times with dichloromethane. The organic layer was dried (MgSO4), evaporated and the crude product purified by distillation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:2]1.S(Cl)(Cl)=O>COCCOCCOC.N1C=CC=CC=1>[S:1]1[C:2]2[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:3]=2[CH:4]=[CH:5]1
Reactant: O=C(O)CCCc1ccsc1
Solvent: c1ccncc1
Solvent: COCCOCCOC
Solvent: O=S(Cl)Cl
Product: O=C1CCCc2ccsc21
Temperature: 70 °C
Yield: 69.3 %

Procedure:
The product from Step D (1.8 g, 11.0 mmol) was dissolved in 2-methoxyethyl ether (2 mL) and added thionyl chloride (0.89 mL, 12.2 mmol) and pyridine (1 drop) and heated to 70° C. for 24 hours. The mixture was purified by column chromatography (silica gel, 0-15% ethyl acetate/hexanes as an eluent) to provide 5,6-dihydro-4H-benzothiophen-7-one (1.16 g, 72%): 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=4.9 Hz, 1H), 6.97 (d, J=4.9 Hz, 1H), 2.89-2.87 (m, 2H), 2.63-2.60 (m, 2H), 2.21-2.16 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(N(CC)CC)C>O1CCCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H]2CN(CC(=O)OC(C)(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.5 g), tert-butyl bromoacetate (0.2 ml) and triethylamine (0.31 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. After filtration, the filtrate was concentrated to a syrup, which was subjected to a chromatography on a silica gel with a mixture of toluene and ethyl acetate (20:1) to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(tert-butoxycarbonylmethyl) piperazine (0.52 g). This compound was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-carboxymethyl-2-(3,4-dimethylbenzyl)piperazine hydrochloride (0.33 g) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:29][CH3:30].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:15]([CH2:29][CH3:30])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)CNc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CC)c1cccc(OCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a solution of ethyl 2-((3-(benzyloxy)phenyl)amino)acetate (1.00 g) in DMF (10 mL) were added potassium carbonate (970 mg) and iodoethane (2.20 g), and the mixture was stirred at 120° C. for 4 hr. The mixture was allowed to cool to room temperature, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (960 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:20]=[C:19](Cl)[CH:18]=[C:17]([C:22]#[N:23])[C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[CH:3]=[N:2]1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.O>C1COCC1.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:20]=[C:19]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]4[NH:31][C:32]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:38])[CH:18]=[C:17]([C:22]#[N:23])[C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1ccc2cn[nH]c2c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1ccc2cn[nH]c2c1
Yield: 62 %

Procedure:
A solution of methyl 2-(1H-indazol-6-ylamino)-6-chloro-4-cyanonicotinate (115 mg, 0.351 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (90 mg, 0.421 mmol) and Et3N (0.073 mL, 0.526 mmol) in THF (1 mL) was stirred at reflux overnight. Water and EtOAc were added to the mixture. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with H2O and brine, dried over MgSO4, and evaporated. The residue was rinsed with EtOAc to give the title compound as yellow solid (110 mg, 62.0%). 1H NMR (500 MHz, CDCl3) δ ppm 1.00-1.86 (m, 17H), 3.84 (s, 3H), 3.91 (br s, 1H), 4.12 (br s, 1H), 6.51 (s, 1H), 6.63 (d, J=8.79 Hz, 1H), 7.13 (d, J=8.30 Hz, 1H), 7.97 (s, 1H), 8.03 (br s, 1H), 10.71 (br s, 1H), 12.87 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][O:19][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:29])=[CH:21][CH:22]=2)=[O:28])[CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Reactant: Cc1ccc(N=C=O)cc1
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccc(C)cc2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:15]=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24]>C1COCC1>[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH:24][C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[S:16]
Reactant: S=C=Nc1ccccc1Oc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: C1CCOC1
Product: N[C@@H]1CCCC[C@H]1NC(=S)Nc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.6 g of 2-phenoxyphenyl isothiocyanate in 10 ml of THF was added to a solution of 0.8 g of trans-1,2-diaminocyclohexane in 30 ml of THF, and the mixture was stirred at room temperature for about 4 hours. The solvent was evaporated and the residue was subsequently subjected to column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of methylene chloride, 5 parts of methanol and 1 part of concentrated aqueous ammonia solution, giving the desired compound as an amorphous oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH:14][C:15]([NH2:17])=S)[CH:3]=1.[OH-].[K+].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([NH:14][C:15]#[N:17])[CH:3]=1
Reactant: NC(=S)Nc1cc(F)ccc1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#CNc1cc(F)ccc1-c1ccccc1

Procedure:
A suspension of N-(4-fluoro-2-biphenylyl)thiourea (11 g) in water (70 ml) was reacted with a solution of potassium hydroxide (25.2 g) in water (70 ml). Lead acetate trihydrate (17 g) in water (70 ml) was added and the reaction mixture heated at 90°-95° C. for 40 minutes to give 4-fluoro-2-biphenylylcyanamide (m.p. 68°-70° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:25])[NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])=[O:25]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C(N)C(=O)NC1c2ccccc2CC1O

Procedure:
Compound 61 was kept in DCM-TFA 2:1 (2 mL) for 60 min at RT. The solution was co-evaporated with toluene to dryness.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:37]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:33]4[CH:34]=[N:35][N:36]([CH2:38][CH2:39][N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)[CH:37]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cnn(CCN4CCOCC4)c3)ccc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine were reacted to give 269. MS: (ESI+)=512.2
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH:12]=[CH2:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]([CH:12]=[CH2:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOCC3)cc21

Procedure:
2.6 g of 7-chloro-6-fluoro-4-oxo-1-vinyl-1,4-dihydro-quinoline-3-carboxylic acid, 3.5 cm 3 of morpholine and 30 cm3 of dimethylsulphoxide were heated for 15 hours under reflux. The solvent was removed by distillation under reduced pressure and the residue was taken up in 20 cm3 of ethanol. The insoluble solid was separated and recrystallised from 8 cm3 of a 1:1 (by volume) mixture of methylcellosolve and ethanol. 0.4 g of 6-fluoro-7-morpholino-4-oxo-1-vinyl-1,4-dihydroquinoline-3-carboxylic acid, m.p. 218°-220° C., was obtained.