Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:16])(=[O:4])[CH3:3].[NH2:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[C:20]([Cl:32])[CH:19]=1>>[ClH:16].[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22](=[O:23])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([Cl:32])[CH:19]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(C(=O)c2ccccc2)c(Cl)c1
Agent: Cl
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(C(=O)c4ccccc4)c(Cl)c3)c2c1
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline hydrochloride was reacted with 4-amino-2-chlorobenzophenone to give 6-acetoxy-4-(4-benzoyl-3-chloroanilino)quinazoline hydrochloride salt in 47% yield, m.p. >250° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OC)OC)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:25]=[CH:24][N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluorobenzyl)glycinamide (61.5 g, 152 mmol) and p-toluenesulfonic acid monohydrate (3 g) in toluene (450 mL) was stirred at 75° C. for 5 days. Each day an additional 3 g of toluenesulfonic acid was added. The resultant reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue dissolved in dichloromethane. The organic solution was washed successively with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluting with dichloromethane and then 5% ethyl acetate in dichloromethane. Appropriate fractions were collected and concentrated under vacuum. Residual ethyl acetate and dichloromethane was removed by co-evaporation with toluene for 3 time for subsequent hydrogenation. The residue was triturated with hexane, and filtered to provide the cyclization product as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 78.1 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (290 mg, 0.934 mmol) was reacted with tert-butyl 4-aminobenzylcarbamate (312 mg, 1.40 mmol) to afford the desired product (362 mg, 78%) as a yellow solid: ESI MS m/z 496 [C25H26BrN3O3+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][N:5]=[C:4]([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])(=[O:9])=[O:8])[CH2:3]1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:56])(=O)=O)=CC=1>C(#N)C>[F:56][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:19])[F:20])[S:7]([C:4]1[CH2:3][C:2]([CH3:22])([CH3:1])[O:6][N:5]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(C)CC(S(=O)(=O)Cc2ccccc2OC(F)(F)F)=NO1
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: CC#N
Product: CC1(C)CC(S(=O)(=O)C(F)c2ccccc2OC(F)(F)F)=NO1
Yield: 69.2 %

Procedure:
5,5-Dimethyl-3-(2-trifluoromethoxy-phenylmethanesulfonyl)-4,5-dihydroisoxazole (0.2 g, 0.59 mmol) was dissolved in acetonitrile (5 ml) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (Verkade's base) (0.44 ml, 1.24 mmol) was added dropwise at room temperature. After 5 minutes N-fluorobenzene-sulfonimide (NFSI) (393 mg, 1.24 mmol) was added in one portion. After 10 minutes the reaction was quenched by addition of water (10 ml). The mixture was acidified by addition of aqueous hydrochloric acid (2M) and extracted several times with ethyl acetate (3×10 ml). The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution and with water, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.68 of Table 27) as colourless oil (145 mg, 69% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[C:9](/[N+:11]([O-:13])=[O:12])\[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH:8]([C:7]3[C:2]([CH3:1])=[C:3]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:4]=[CH:5][CH:6]=3)[CH:9]([N+:11]([O-:13])=[O:12])[CH3:10])=[CH:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: C/C(=C\c1cccc(NC(=O)OCc2ccccc2)c1C)[N+](=O)[O-]
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)[N+](=O)[O-]
Temperature: 140 °C
Yield: 31.3 %

Procedure:
A mixture of (E)-benzyl (2-methyl-3-(2-nitroprop-1-en-1-yl)phenyl)carbamate (5.16 g, 15.8 mmol) and 6-bromo-1H-indole (6.20 g, 31.6 mmol) was heated neat at 140° C. overnight. The crude reaction mixture was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (20%-35%-50%) to give benzyl (3-(1-(6-bromo-1H-indol-3-yl)-2-nitropropyl)-2-methylphenyl)carbamate (2.58 g, 4.94 mmol, 31% yield) as a burgundy oil/solid and as a 1:1 mixture of diastereomers.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:43](=[O:44])[NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Product: O=C(Nc1ccccc1)N(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.396 mmol) of (2S*,4R*)-2-benzyl-1-(3.5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine are reacted with 45 mg (0.377 mmol) of phenyl isocyanate in analogy to Example 16a. The title compound ##STR80## is obtained as solid residue (129 mg, 52%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.42, FD-MS: M+ =622, 624.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([NH2:54])(=[O:53])[C:46]1[C:47](=[CH:49][CH:50]=[CH:51][CH:52]=1)O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([C@@H:7]1[C:8](=[O:25])[O:9][C@H:10]1[CH2:11][C@@H:12]([O:24][C:52]1[CH:51]=[CH:50][CH:49]=[CH:47][C:46]=1[C:45]([NH2:54])=[O:53])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC(=O)c1ccccc1O
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)Oc1ccccc1C(N)=O
Temperature: 0 °C
Yield: 49.5 %

Procedure:
1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4 Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:10][C:11]([C:13]1([C:43]([OH:45])=[O:44])[O:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][CH:23]([N:25](C(OC(C)(C)C)=O)[CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[OH:28])[CH3:24])=[CH:21][C:15]=2[O:14]1)=[O:12])[C:6]([O:8][CH3:9])=[O:7])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][O:8][C:6]([CH:5]([O:10][C:11]([C:13]1([C:43]([OH:45])=[O:44])[O:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][CH:23]([NH:25][CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[OH:28])[CH3:24])=[CH:21][C:15]=2[O:14]1)=[O:12])[C:3]([O:2][CH3:1])=[O:4])=[O:7]
Reactant: COC(=O)C(OC(=O)C1(C(=O)O)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(OC(=O)C1(C(=O)O)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1)C(=O)OC
Temperature: 23 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a stirred solution of 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonyl-methyl ester (330 mg, 0.50 mmol) and CH2Cl2 (10 mL) was added trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol). After stirring at 23° C. for 1 h, additional trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol) was added. After a total of 22 h, the mixture was quenched with 5 mL of sat. aq. NaHCO3, and extracted with 3×30 mL of EtOAc. The combined organics were washed with 1×50 mL of brine, dried over MgSO4, filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with CHCl3 /MeOH (20/1 to 10/1) gave 145 mg (52%) of product as a white gum; 1H NMR (300 MHz, CDCl3): δ 1.33 (m, 3H), 1.70-2.40 (brm, 2H), 2.73-2.90 (brt, 1H), 3.04-3.30 (m, 2H), 3.37-3.53 (m, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 4.80 (s, 2H), 4.81 (s, 2H), 5.40 (m, 1H), 6.73-6.93 (complexm, 4H), 7.15-7.32 (m, 2HO, 7.43 (s, 1H); MS (ES) m/z (relative intensity): 566 (M+, 80), 508 (M+ -CO2CH3 +H, 100), 450 (M+ -2CO2CH3 +2H, 30).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12](O)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:54][C:55]([NH2:59])([CH3:58])[CH2:56][NH2:57]>CN(C=O)C>[NH2:59][C:55]([CH3:58])([CH3:54])[CH2:56][NH:57][C:12]([C:8]1[N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:5]2=[N:10][C:9]=1[CH3:11])=[O:13]
Reactant: CC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.20 mmol), 96 mg (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.30 mmol) and 80 mg of 4-methylmorpholine (0.79 mmol) were initially charged in 1 ml of DMF. 35 mg of 2-methylpropane-1,2-diamine (0.40 mmol) were then added, and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product was taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated and lyophilized. This gave 38 mg of the title compound (45% of theory).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([F:4])[F:3].ClC1C=CC=C(C(OO)=[O:19])C=1.[OH-].[Na+]>ClCCl>[F:1][C:2]([F:4])([F:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][n+]1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
5.1 g (35 mmol) of trifluoromethylpyridine were dissolved at room temperature in 100 ml of dry dichloromethane, admixed with 17.3 g of m-chloroperbenzoic acid and stirred at room temperature for 72 h. Thereafter, the mixture was admixed with 1 N sodium hydroxide solution and extracted four times with dichloromethane; the combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was taken up in water, stirred and filtered, and the filtrate was concentrated under reduced pressure. 65.3 was obtained in 47% yield. 1H NMR: 8.46, d, 1H, 7.96, d, 1H, 7.7, m, 1H, 7.5, m, 1H.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CCO>[C:21]([O:20][C:19](=[O:25])[NH:18][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][NH:10][C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:17][CH2:16]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2Cl)CC1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a solution of the above 5-chloro-2,4-dichloropyrimidine (73 mg, 0.4 mmol) in EtOH (2 mL) were added tert-butyl trans-4-aminomethylcyclohexylcarbamate (100 mg, 0.44 mmol) and DIPEA (77 μL, 0.44 mmol). The reaction mixture was heated at 40° C. for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc. The solution was washed with brine. The aqueous layer was re-extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield 148 mg (99%) of {4-[(2,5-dichloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.N1C=CN=C1.C(N(CC)CC)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O.O>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCC1(CO[Si](C)(C)C(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 10 ml of N,N-dimethyl formamide, and 0.14 g of imidazole was added thereto. The mixture was cooled in ice-water bath, and 0.87 ml of triethyl amine (6.2 mmol) was added thereto. After stirring for 5 minutes, 0.88 g of tert-butyldimethylsilyl chloride (5.8 mmol) in 10 ml of N,N-dimethyl formamide was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with 10 ml of water, and extracted twice using 20 ml of dichloromethane for each time. The combined dichloromethane extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.28 g of concentrate (yield 87.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:36]1([Mg]Cl)[CH2:40][CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]C1CCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2C2CCCC2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a −78° C. solution of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added cyclopentyl magnesium chloride (0.17 mL, 1.0 M in diethyl ether). The resulting solution was stirred under nitrogen less than 1 hour with warming to room temperature. The reaction was poured into water and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO2, 2:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.1328 g, 94%). mp 155-157° C. 1H NMR (300 MHz, DMSO d6) δ 1.50 (m, 2H), 1.66 (m, 2H), 1.79 (m, 2H), 2.09 (m, 2H), 2.90 (m, J=8 Hz, 1H), 3.26-3.37 (3H, obstructed by H2O), 7.49-7.63 (m, 3H), 7.71 (m, 3H), 7.97 (s, 1H), 8.10 (m, 2H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21ClN2O3S: C, 61.60; H, 4.93; N, 6.53. Found: C, 61.48; H, 4.81; N, 6.22.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[C:17]([N:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22])[N:16]=[C:15]([C:27]([OH:29])=O)[CH:14]=1)=O)(C)(C)C.[C:38]1([CH:44]2[CH2:48][CH2:47][CH2:46][NH:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.NC(C)(CC1C=CC=CC=1)COCC1C=C(N(S(C)(=O)=O)CCC)N=C(C(NC(C2C=CC(F)=CC=2)C)=O)C=1>>[NH2:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([C:27]([N:45]2[CH2:46][CH2:47][CH2:48][CH:44]2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[N:16]=[C:17]([N:19]([CH2:20][CH2:21][CH3:22])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)n1)S(C)(=O)=O
Reactant: c1ccc(C2CCCN2)cc1
Agent: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)NC(C)c2ccc(F)cc2)n1)S(C)(=O)=O
Product: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)N2CCCC2c2ccccc2)n1)S(C)(=O)=O

Procedure:
N-{4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-6-[(2-phenylpyrrolidin-1-yl)carbonyl]pyridin-2-yl}-N-propylmethanesulfonamide was prepared from 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylic acid (intermediate VII) and 2-phenylpyrrolidine following a similar procedure as described for the preparation of 4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[1-(4-fluorophenyl)ethyl]-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxamide. HRMS (ES, M+H) calcd. for C31H40N4O4S: 565.2843, found: 565.2859.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:3]([O:5]CC)=O.[CH:20]([C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[CH2:21].[BH4-].[Na+].[N:32]#[C:33][OH:34]>>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:2]1([CH3:19])[N:1]([CH2:21][CH2:20][CH:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[OH:23])[C:33](=[O:34])[NH:32][C:3]1=[O:5])([OH:16])=[O:15]
Reactant: CCOC(=O)CCCCCCC(C)(N)C(=O)OCC
Reactant: N#CO
Reactant: C=CC(=O)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(CCCCCCC(=O)O)C(=O)NC(=O)N1CCC(O)C1CCCCC1

Procedure:
By sequential reaction of diethyl 2-amino-2-methylnonanedioate with cyclohexyl vinyl ketone, sodium borohydride, and cyanic acid according to the general procedure described in Example 105, 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-5-methylhydantoin was obtained as a mixture of diastereomers. Separation by high performance liquid chromatography gave the individual racemic diastereomers as colourless gums, the less polar isomer having Rf. 0.52 relative to Rf. 0.48 for the more polar isomer on SiO2 in chloroform-methanol-acetic acid 90:5:5. The less polar isomer gave characteristic 'H n.m.r. signals at δ9.34 (1H, broad singlet, exch., NH), 5.83 (2H, broad singlet, exch., CO2H and OH), 3.6, 3.3 and 3.1 (3H, three multiplets, C-13 protons and C-15 methine), 2.31 (2H, triplet, CH2 adjacent to CO2H) and 1.39 (singlet, isolated CH3) in CDCl3. The more polar isomer gave characteristic 'H n.m.r. signals at δ9.23 (1H, broad singlet, exch., NH), 5.73 (2H, broad singlet, exch., CO2H and OH), 3.38 (3H, multiplet, C-15 methine and C-13 protons), 2.32 (2H, triplet, CH2 adjacent to CO2LH) and 1.40 (singlet, isolated CH3) in CDCl 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH2:39][CH:40]([OH:44])[CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:44][CH:40]([CH2:41][CH2:42][CH3:43])[CH2:39][CH2:38][CH3:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: CCCC(O)CCC
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(CCC)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 79.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-heptanol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 76%).