Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C@@H:8]([CH3:20])[CH2:7]1)[CH3:2].[C:29](Cl)([Cl:31])=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:28])[N:5]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]([C:29]([Cl:31])=[O:30])[C@@H:8]([CH3:20])[CH2:7]1)[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)Nc2cc(OC)c(OC)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)Cl)c2cc(OC)c(OC)cc21
Yield: 92 %

Procedure:
To a solution of cis-benzyl-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 66) (103 mg, 0.268 mmol) in toluene (2.5 mL) was added phosgene (1.0 mL of a 1.93M solution in toluene) and the reaction mixure was heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo to give the desired carbamoyl chloride (110 mg, 92%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>ClCCl.CO>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:42]([N:41]([CH3:45])[CH3:40])=[O:43])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN(C)C(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (50 mg, 0.12 mmol, Example 1) was dissolved in dichloromethane (5 mL) and methanol (1 mL). Triethylamine (0.016 mL, 0.12 mmol) was added followed by dimethylcarbamyl chloride (10.72 μL, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, the crude dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by HPLC yielding 4-((2-hydroxyethyl)(phenyl)amino)-N,N-dimethyl-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide (19.0 mg, 33%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:42][N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CN1Cc2c(CN3CCCC3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(CN4CCCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 109A. MS (ES+): m/z 663.51 (100) [MH+]; HPLC: tR=0.74 min (UPLC, purity).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=2)[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCc1c(-c2ccc3cc(O)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
To a stirred solution of the 1-benzyl-2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole (109.0 g, 251 mmol) in CH2Cl2 (1000 mL) under N2 at −78° C. was added BBr3 (1 M in CH2Cl2, 302 mL), dropwise, over 1.5 h. After the addition, the reaction was warmed to 0° C. and stirred for 2.5 h then warmed to rt. After a total of 5 h the reaction mixture was cooled to 0° C. and quenched with water (250 mL). The mixture was stirred overnight then rotovap'd to a residue. The residue was partitioned between EtOAc (1500 mL) and H2O (500 mL). The layers were shaken, separated, and the organic layer was washed with H2O (2×250 mL), brine (2×250 mL), dried over Na2SO4, filtered, rotovap'd and dried in vacuo to give a viscous black goo (114 g). The residue was dissolved in CHCl3 and flashed on silica (2000 g). The column was eluted with hexane and 8% EtOAc/Hexane. The product was collected, filtered, rotovap'd and the residue triturated with hexane then dried to give the product as an off-white solid (89.2 g, 213 mmol, 85%) with mp 96-100° C. 400 mg of the crude solid was recrystallized from hexane to give desired product as an off-white solid (311 mg) with mp 97-100° C.; 1H NMR (DMSO-d6) δ 0.73 (t, J=6.7 Hz, 3H), 1.10-1.20 (m, 4H), 1.51-1.60 (m, 2H), 2.67 (t, J=7.3 Hz, 3H), 5.29 (s, 2H), 6.82 (d, J=7.2 Hz, 2H), 7.04-7.20 (m, 7H), 7.30-7.35 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.73-7.78 (m, 3H); IR (solid) 3380, 2920, 1610, 1200, 740 cm−1; mass spectrum [ES], m/z 420 (M+H)+;
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[CH3:42][N:43](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:43][CH3:42])=[O:30])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC)cc3OC)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-162), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.05 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.16 mL (0.32 mmole) of 2M methylamine in tetrahydrofuran was then added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (60:40) to give 0.036 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-164).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17](S(C)(=O)=O)[N:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[NH:36]C1C=CC=CC=1>C(#N)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([NH:36][C:27]2[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=2)[N:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)(=O)=O)ncc3c2)ccn1
Solvent: CC#N
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc5ccccc5c4)ncc3c2)ccn1
Temperature: 82.5 °C

Procedure:
N-methyl[4-(2-methylsulfonylquinazolin-6-yloxy)(2-pyridyl)]carboxamide 15 (1 eq) was treated with 2-naphthylaniline (2 eq) in acetonitrile (1 M) and heated at 80-85° C. The mixture was evaporated and purified on preparative chromatography to give the product.
Reaction SMILES: [Na+].[I-:2].ClN1C(=O)CCC1=O.[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)=[CH:20][CH:19]=2)=[O:15])[CH3:12].[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O>[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([C:24]=1[I:2])=[CH:22][C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1)=[CH:20][CH:19]=2)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2[nH]1
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc2c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaI (2.04 g, 14 mmol) in acetone (10 mL) was added dropwise to a stirred solution of N-chlorosuccinimide (1.83 g, 14 mmol) in acetone (10 mL) protected from light. After 15 min, a solution of 5-(4-trifluoromethylphenyl)indole-2-carboxylic acid ethyl ester (3.80 g, 11 mmol; see step (a) above) in acetone (60 mL) was added dropwise, followed by stirring for 2 h at rt. The mixture was poured into Na2S2O3 (aq, 10%, 250 mL) and extracted with EtOAc (200 mL). The combined extracts were washed with NaHCO3 (aq, sat), water and brine, dried (Na2SO4) and concentrated. The residue was treated with petroleum ether to give the sub-title compound. Yield 4.88 g (93%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N+](=[CH2:15])=[N-]>>[CH3:15][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: C=[N+]=[N-]
Product: COC(=O)Cc1ccc(SC)cc1

Procedure:
(4-Methylsulfanyl-phenyl)-acetic acid was treated with an etheral solution of diazomethane until completion of esterification. The solvent was evaporated, the residue triturated in hexane/ether, and filtered to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)[CH2:9][CH3:10].[H-].[Na+].CN(C)C=O.CS(O[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[CH:43][CH:42]=[CH:41]2)[CH:35]=1)(=O)=O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:20][C:2]([CH3:19])([CH3:1])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH:44]=[CH:43][CH:42]=[CH:41]3)[CH:35]=2)[CH:13]=1)[CH2:9][CH3:10]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Reactant: CS(=O)(=O)OCc1cccc(-n2cccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cccc(-n3cccc3)c2)c1
Yield: 70 %

Procedure:
100 mg of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine was dissolved in 1 ml of anhydrous tetrahydrofuran, and 20 mg of 60% oily sodium hydride was added to the solution with ice cooling and stirring, and the mixture was stirred for 10 minutes. To the resulting solution was added 1 ml of a dimethylformamide solution of 100 mg of 3-(1-pyrrolyl)benzyl methanesulfonate, and the mixture was stirred overnight at room temperature. The solution was extracted by adding 20 ml of water and 30 ml of ethyl ether. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 20 g, eluting solvent: hexane/ethyl acetate=10/1→5/1) to give 110 mg (yield 70%) of the captioned compound as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:33]1[C:38]([F:39])=[CH:37][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([C:33]3[C:38]([F:39])=[CH:37][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:35][N:34]=3)[OH:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ncc(C(F)(F)F)cc1F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][CH2:10][CH:11]=O>>[CH3:8][O:9][CH2:10][CH2:11][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC=O
Reactant: Nc1ccccc1
Product: COCCNc1ccccc1

Procedure:
The title compound was prepared from aniline and methoxyacetaldehyde by the same method as described for Example 5, part A. The residue was purified by flash chromatography on silica gel (ethyl acetate:hexanes/1:15) to give a pale yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH:11]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:1]([C:8]1[CH:9]=[CH:10][C:5]([CH:11]2[CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)=[CH:6][CH:7]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C1CC(c2ccccc2)C1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C1CC(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 8 h

Procedure:
Fuming nitric acid (0.54ml.) was added dropwise to a stirred solution of methyl 3-phenylcyclobutanecarboxylate (950mg.) in acetic anhydride (5ml.) and glacial acetic acid (0.25ml.) at -5° C. The reaction mixture was set aside overnight at room temperature then poured onto ice and extracted with ethyl acetate (3 × 20ml.) The ethyl acetate solution was dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue on a column of "Florisil" (25g.), eluting with toluene, gave methyl 3-(4-nitrophenyl)cyclobutanecarboxylate as a pale yellow oil. The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (δ values):- ##STR16##
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29][N:30]([CH3:35])[C:31](=[O:34])[CH2:32][Cl:33]>>[ClH:33].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:32][C:31]([N:30]([CH3:35])[CH3:29])=[O:34])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: CN(C)C(=O)CCl
Agent: Cl
Product: CN(C)C(=O)CN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m. p. 145° C. and MS: m/e=455.6 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and N,N-dimethyl-2-chioroacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH:13](Cl)[CH3:14].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(Cl)Br
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 102.4 %

Procedure:
To a stirred mixture of 3,4-Dichloro-phenylacetonitrile (4.65 g. 25 mmol) triethylbenzylammonium chloride (0.2 g) and 1-bromochoroethane (4.2 ml, 50 mmol), 50% sodium hydroxide (16 ml, 200 mmol) was added dropwise at 50° then the reaction was stirred at 50° for 10 hrs. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc (×3). The layers were separated, washed with water (×3) and brine, then dried over MgSO4. Evaporation of the solvent under reduced pressure afforded the title compound (5.43 g) which was then recrystallized from Et2O/hexanes as a pale pink solid (4.49 g, 85%). Lc/MS(ES) m/e 212 [M+H]+.
Reaction SMILES: [S:1]([C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)C1C=CC(O)=CC=1.CN([CH:19]=[O:20])C>>[O:20]([C:19]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:1])[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:1]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Sc2ccc(O)cc2)cc1
Product: Sc1ccccc1Oc1ccccc1S
Reaction time: 24 h
Yield: 75 %

Procedure:
4.91 g (0.0225 mol) of 4,4′-thiodiphenol was dissolved in DMF, and then an aqueous solution of 1.26 g (0.0225 mol) of NaSH was added thereto. The mixture was stirred for 24 hours. The mixture was washed with water several times and filtered, and thus oxydibenzenethiol was obtained. The oxydibenzenethiol thus obtained was dissolved in methylene chloride, and then 1.50 g (0.0148 mol) of triethylamine (TEA) was added thereto. The mixture was stirred for 10 minutes. Subsequently, 1.34 g (0.0148 mol) of acyloyl chloride was added thereto, and the mixture was stirred. After 24 hours, the mixture was washed several times with distilled water and several times with a 1 wt % aqueous hydrochloric acid solution, the organic layer was separated, and the solvent was eliminated. A residue remaining thereafter was purified by a chromatographic method and using hexane and ethyl acetate. An aqueous solution containing 0.89 g (0.0158 mol) of KOH was added thereto, 1.462 g (0.0158 mol) of epichlorohydrin was added thereto, and the mixture was stirred at normal temperature. After 36 hours, chloroform was added to the mixture to extract the product, and then the extract was washed several times with distilled water. Epichlorohydrin and the solvent were evaporated, and then a compound represented by the Formula (1-8) was separated by a chromatographic method and using hexane and ethyl acetate at a weight ratio of 2:1. The compound was purified to a purity of 99% or higher (yield: 75%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cccc(OCCCBr)c1
Reaction time: 5 h

Procedure:
3-Cyanophenol (10.0 g, 84 mM), 3-bromopropanol (20.3 mL, 114 mM), triphenylphosphine (29.7 g, 114 mM) were stirred in anhydrous THF (40 mL) at room temperature and treated with diethylazodicarboxylate (17.8 mL, 114 mM) dropwise over 5 min. under an atmosphere of nitrogen. This mixture stirred for about 5 hours then diluted with ether (500 mL) and filtered through Celite™. The filtrate was concentrated to a reddish oil which was again dissolved in ether (250 mL), diluted with hexanes (200 mL) and filtered. The filtrates were concentrated then filtered through a silica pad (300 g) eluting with 35% acetone/hexanes to collect the desired product as a yellow oil, 16.85 g. This material was used in its crude form.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[OH-:12].[Na+]>O>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[N:7][C:2]([OH:12])=[CH:3][CH:4]=1
Reactant: [OH-]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C(F)(F)F)nn1

Procedure:
A mixture of 6-chloro-3-trifluoromethylpyridazine (10 g, 54. 9 mmol) (prepared by following the procedure described in Goodman, A. J.; Stanforth, S. P.; Tarbit B. Tetrahedron 1999, 55, 15067-15070) and sodium hydroxide (8 g, 0.7 mmol) in water (150 ml) was stirred at reflux for 5 h. After this period, the solvent was evaporated in vacuo and the crude product dried at 60° C. under vacuum for 16 h. to yield D3, mixed with sodium chloride, (16.2 g,>100%) as a solid. C5H3F3N2O requires 164; Found 165 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21](OC)=[O:22])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][OH:22])=[CH:15][CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc2nnc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CO)cc2c1O
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a suspension of methyl 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-cinnolinecarboxylate (Prep 5, 0.48 g) in 40 mL THF is added lithium aluminum hydride (2.60 μL) dropwise. The reaction turns a dark green color. After 1 h, the reaction is quenched carefully with water, 15% NaOH, and water again. The reaction is filtered to remove aluminum salts. The filtrate is concentrated and the resulting residue is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (2L), 5.5% MeOH/CH2Cl2 (2L)) affords the desired product (0.23 g, 52%). Physical characteristics are as follows: m.p. 296-298° C.; 1H NMR (300 MHz, DMSO-d6) δ10.12, 8.14, 7.84, 7.74, 7.41, 5.50, 4.66, 4.56; IR (drift) 2922, 2873, 1647, 1602, 1555, 1490, 1358, 1183, 1022, 930, 919, 836, 808, 722, 684 cm−1; MS (FAB) m/z 344 (MH+), 346, 344, 287, 229, 153, 133, 125, 121, 107, 103; HRMS (FAB) calcd for C17H14ClN3O3+H1 344.0802, found 344.0805.