Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[NH:17][C:16](=[S:19])[NH:15][C:14]=3[C:13](=[O:20])[N:12]3[CH2:21][CH2:22][N:23]=[C:11]23)=[CH:5][CH:4]=1.I[CH3:25]>[OH-].[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[NH:17][C:16]([S:19][CH3:25])=[N:15][C:14]=3[C:13](=[O:20])[N:12]3[CH2:21][CH2:22][NH:23][CH:11]23)=[CH:5][CH:4]=1
Reactant: CI
Reactant: O=C1c2[nH]c(=S)[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc2c([nH]1)N(Cc1ccc(Cl)cc1)C1NCCN1C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Procedure 97 (2.4 g., 0.0068 mole) in 0.1N NaOH (85 ml.), iodomethane (1.94 g., 0.0136 mole) was added and the mixture stirred at room temperature for 16 hrs. The insolubles were collected and recrystallized from methoxyethanol to give 1.3 g. of product, m.p. 296°-297°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([S:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:38])=[O:37])[CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(1-phenylsulfonyl-piperidin-4-yl)-urea was prepared starting from intermediate N and benzenesulfonyl chloride. MS calcd. for C28H28ClN4O4S [(M+H)+] 551.1, obsd. 551.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:38]([O:43]C)(OC)[O:39]C.Cl>O1CCCC1>[C:21]1([N:12]2[C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([B:38]([OH:43])[OH:39])=[CH:7][CH:6]=4)=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
In a 300-mL three-neck flask was put 8.0 g (20 mmol) of the 3-(4-bromophenyl)-9-phenyl-9H-carbazole obtained in Reaction Scheme (b-1), the atmosphere in the flask was replaced with nitrogen, 100 mL of dehydrated tetrahydrofuran (abbreviation: THF) was then added to the flask, and the temperature was lowered to −78° C. Into this mixture solution, 15 mL (24 mmol) of a 1.65 mol/L n-butyllithium hexane solution was dropped, and the mixture solution with the n-butyllithium hexane solution added was stirred for 2 hours. To this mixture, 3.4 mL (30 mmol) of trimethyl borate was added, and the mixture with the trimethyl borate added was stirred at −78° C. for 2 hours and at room temperature for 18 hours. After the reaction, 1M diluted hydrochloric acid was added to this reaction solution until the solution became acid, and the solution with the diluted hydrochloric acid added was stirred for 7 hours. This solution was subjected to ethyl acetate extraction, and the obtained organic layer was washed with a saturated saline. After the washing, magnesium sulfate was added to the organic layer to adsorb moisture. This suspension was filtered, and the obtained filtrate was concentrated, and hexane was added thereto. The mixture was irradiated with supersonic waves and then recrystallized, so that 6.4 g of a target substance was obtained as a white powder in a yield of 88%. A reaction scheme of Step 2 is shown in (b-2) given below.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>CN(C)C=O>[N:21]1([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]2=3)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Add 4.0 gm of methyl 6,11-dihydro-11-chlordibenz[b,e]oxepin-2-carboxylate to a 78° C. solution of 2.0 gm of imidazole in 15 ml of dimethylformamide. Stir under a nitrogen atmosphere for 1 hour. Cool to room temperature and pour into 25 ml of water. Extract twice with 125 ml of ether. Wash the combined ether extracts twice with 50 ml of water and with 25 ml of saturated aqueous sodium chloride. Dry over anhydrous sodium sulfate and evaporate to dryness to obtain the title product (Yield 3.12 gm).
Reaction SMILES: [C:1]([CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O)#[N:2].Cl.[F:22][C:23]([F:28])([F:27])[CH2:24][NH:25][NH2:26].C(N(CC)CC)C>C(O)C>[CH2:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4]1[CH:3]=[C:1]([NH2:2])[N:25]([CH2:24][C:23]([F:28])([F:27])[F:22])[N:26]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNCC(F)(F)F
Reactant: N#CCC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1cc([C@H]2CCCN2C(=O)OCc2ccccc2)nn1CC(F)(F)F

Procedure:
To a solution of Example 69A (3.0 g, 11 mmol) in ethanol (10 mL) was added (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt (2.3 g, 11 mmol) and triethylamine (1.84 mL, 13.2 mmol) at rt. The solution was heated under reflux for 4 h. After cooling, the reaction mixture was concentrated and the residue was separated by flash chromatography to give Example 69B. Yield: 3.5 g (88%). MS (DCI): m/z 369 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.[Cl:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>O1CCCC1>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:28]([NH:27][CH2:26][CH2:25][Cl:24])=[O:29])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C=NCCCl
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Solvent: C1CCOC1
Product: O=C(NCCCl)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Yield: 52.2 %

Procedure:
N1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (400 mg), 2-chloroethyl isocyanate (150 mg) and tetrahydrofuran (5 ml) were stirred at 80° C. for 1.5 hours. The mixture was returned to room temperature, silica gel was added, and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) to obtain 280 mg of a colorless powder.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([Cl:27])=[CH:21][NH:22]2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:27][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]=[C:8]=[S:9])[NH:22][CH:21]=1
Reactant: Nc1cccc2[nH]cc(Cl)c12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: S=C=Nc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
4-Dimethylaminopyridine (0.031 g, 0.256 mmol) and di-2-pyridyl thionocarbonate (0.983 g, 4.23 mmol) are added to a solution of 4-amino-3-chloroindole (0.655 g, 2.82 mmol) in methylene chloride. The resulting mixture is stirred at room temperature for 1 hour. The volatile organics are removed by rotary evaporation and the crude residue is purified via silica gel column chromatography using 20% ethyl acetate/hexanes as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.511 g of 3-chloro-4-isothiocyanatoindole as a yellow solid (96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[C:10](=O)([O:13]C)[O:11][CH3:12].[H-].[Na+].CO>C1COCC1>[OH:8][C:5]1[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][C:4]=1[C:10]([O:11][CH3:12])=[O:13]
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a cooled (0° C.) solution of 4,4-dimethylcyclohexanone (21 g, 0.17 mol) and dimethyl carbonate (45 g, 0.50 mol) in THF (400 mL) was added NaH (60% wt/wt in mineral oil, 17 g, 0.43 mol) portionwise over 30 minutes. The resulting slurry was allowed to stir at ambient temperature for 30 minutes followed by two hours at reflux. The reaction mixture was cooled (0° C.) and MeOH (30 mL) was added dropwise over 20 minutes. The resulting slurry was partitioned between 10% aqueous citric acid and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by vacuum distillation provided methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (22.5 g, 75% yield). 1H NMR (400 MHz, CDCl3) δ 12.15 (s, 1H), 3.75 (s, 3H), 2.29 (t, 2H), 2.03 (s, 2H), 1.44 (t, 2H), 0.96 (s, 6H); MS (EI) for C10H16O3: 184 (M+).
Reaction SMILES: C[O:2][C:3]1[C:19]([C:20]#[N:21])=[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[O:10][C:6]2=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[OH:2][C:3]1[C:19]([C:20]#[N:21])=[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:10][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3c(C#N)c(OC)ccc3o2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1c(O)ccc2oc(-c3ccc(O)cc3)cc12
Temperature: 200 °C
Yield: 84.7 %

Procedure:
5-Methoxy-2-(4-methoxyphenyl)-benzofuran-4-carbonitrile 134 (0.088 g, 0.31 mmol) was placed in a sealed tube along with pyridine hydrochloride (enough to fill the volume of the tube by one-half) and heated at 200° C. for 2.5 hours. The reaction was dissolved into a mixture of ethyl acetate and 1 N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organics was washed with 1N HCl (1×), water (1×) and then dried over magnesium sulfate, filtered and concentrated. The resulting material was purified by column chromatography, using 40% ethyl acetate in hexanes as the eluent to yield the desired product 135 (0.066 g, 84.7%) as a light brown solid: Mp>230° C.; 1H NMR (DMSO-d6) δ 10.89 (s, 1 H), 10.03 (s, 1 H), 7.82 (d, 2 H, J=8.6 Hz), 7.72 (d, 1 H, J=8.9 Hz), 7.27 (s, 1 H), 6.90 (d, 2 H, J=8.6 Hz), 6.88 (d, 1 H, J=8.9 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:17]([C:19]#[N:20])[N:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)c(Nc3ccccn3)s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester (prepared as described in Example 1, Step 3) (20.2 mg, 50.4 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (1 mL, 13 mmol) and the mixture stirred under argon at ambient temperature for 30 minutes. The reaction mixture was concentrated in vacuo and the crude 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carbonitrile taken on to the next step in the synthesis without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]=1[CH3:8].[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[C:21]([O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C:3]3=[N:4][C:5]([CH3:10])=[C:6]([Br:9])[C:7]([CH3:8])=[C:2]3[N:1]=[C:10]2[CH2:5][CH2:6][CH2:7][CH3:2])=[CH:13][CH:14]=1)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1nc(Nc2ccc(CCO)cc2)c(N)c(C)c1Br
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)OCCc1ccc(-n2c(CCCC)nc3c(C)c(Br)c(C)nc32)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 9) and pentanoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C@H:26]1([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1>>[C@H:26]1([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH:43][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:25])[CH2:39][CH2:38]2)[C@@H:35]2[N:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:29][CH2:28][CH2:27]1
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (122) (preparation see below) and 1-[(1S,9aR)-1-(octahydro-quinolizin-1-yl)methyl]-piperidin-4-ylamine, 61.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>CO>[CH:34]1([NH:37][CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:29])[F:31])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNC2CC2)cc1)C(F)(F)F
Temperature: 140 °C
Yield: 65.9 %

Procedure:
A 20-mL microwave vial was charged with ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (1.0 g, 1.9 mmol, Intermediate B), cyclopropylamine (4.0 mL, 57 mmol, Alfa Aesar, Ward Hill, Mass.) and MeOH (10.0 mL). The vial was sealed and heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by column chromatography (120 g of silica, 2 to 8% 2M NH3 in MeOH/CH2Cl2) to afford 2-(4-((2S)-2-((cyclopropylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.613 g) as mixture of two isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:28]1[CH2:32][CH:31]=[N:30][C:29]1=[O:33]>>[C:7]([C:6]1[CH:9]=[C:2]([N:30]2[CH2:31][CH2:32][O:28][C:29]2=[O:33])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH:25]3[CH2:27][CH2:26]3)=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: O=C1N=CCO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2C#N)CC1
Yield: 81.6 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 194 and oxazolin-2-one (104 mg), the title compound (352 mg) was obtained.
Reaction SMILES: Cl[CH:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:12](=[O:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH3:23][NH2:24]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:12](=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]2[CH:2]([NH:24][CH3:23])[CH3:3])=[CH:15][CH:16]=1
Reactant: CN
Reactant: COc1ccc(-n2c(C(C)Cl)nc3ccccc3c2=O)cc1
Product: CNC(C)c1nc2ccccc2c(=O)n1-c1ccc(OC)cc1
Temperature: 110 °C
Yield: 98 %

Procedure:
To the neat 2-(1-chloroethyl)-3-(4-methoxyphenyl)-3H-quinazolin-4-one (1.0 g, 3.2 mmol) in a sealed tube was added 40 mL of a methylamine solution (1M in THF, 40 mmol). The tube was sealed and heated to 110° C. 16 h. The resulting solution was cooled to room temperature and concentrated under vacuum to afford the crude product that was purified by flash chromatography (5% MeOH/DCM, silica gel) to afford the title compound (yield 0.97 g, 99%). 1H-NMR (CD3OD): δ 8.28 (m, 1H), 7.93 (m, 1H), 7.86 (m, 1H), 7.65 (m, 1H), 7.43 (m, 1H) 7.33 (m, 1H), 7.19 (m, 2H), 4.09 (q, 1H), 3.92 (s, 3H), 2.75 (s, 3H), 1.51 (d, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[C:25]([O:29][C:30]([NH:32][C@H:33]1[C:37]2([CH2:39][CH2:38]2)[CH2:36][NH:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CS(C)=O>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:35]2[CH2:34][C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:37]3([CH2:38][CH2:39]3)[CH2:36]2)[C:12]([CH3:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Reactant: CC(=O)Nc1c(F)c(F)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)Nc1c(F)c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 80 °C

Procedure:
A mixture consisting of 5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (2.60 g, 7.75 mmol), (7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (2.46 g, 11.6 mmol), triethylamine (1.62 ml, 11.7 mmol) and dimethyl sulfoxide (13 ml) was heated at an outer temperature of 80° C. for 7 hours under a condition of 2.94×108 Pa. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 77%. Also, residual ratio of the starting material was 10%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)[C:17]([CH3:18])=[O:19]
Reactant: CC(=O)CCl
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
A mixture of 4,5-dihydro-6-(p-hydroxyphenyl)-3(2H)pyridazinone (0.55 g), chloroacetone (0.32 g) and potassium carbonate (0.4 g), with a catalytic amount of potassium iodide, was stirred and heated under reflux in acetone (60 ml) for 16 hr. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and evaporated to a gum which was purified by chromatography on Silica gel. Elution with methanol-chloroform (4:96) gave 4,5-dihydro-6-(4-acetonyloxyphenyl)-3(2H)-pyridazinone as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:13]1[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)=[O:19])=[CH:16][N:17]=1)(=O)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:13]2[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]34[CH2:32][CH:27]5[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]5)[CH2:24]3)[CH2:30]4)=[O:19])=[CH:16][N:17]=2)[CH2:3]1
Reactant: OCC1CO1
Reactant: CCS(=O)(=O)c1ncc(C(=O)NCCC23CC4CC(CC(C4)C2)C3)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for ten minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfonyl-5-[2-(adamant-1-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained at 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-[5-(2-[adamant-1-yl]ethylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[C:26]([C:27]([F:30])([F:29])[F:28])=[N:25][N:24]=[N:23]3)[CH:19]=[CH:18][C:17]=2[O:31][CH2:32][CH2:33][CH3:34])[C@@H:9]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O)(C)(C)C.[ClH:48]>O1CCOCC1>[ClH:48].[ClH:48].[CH2:32]([O:31][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[C:26]([C:27]([F:29])([F:28])[F:30])=[N:25][N:24]=[N:23]2)=[CH:21][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:33][CH3:34]
Reactant: CCCOc1ccc(-n2nnnc2C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCOc1ccc(-n2nnnc2C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
From 3{tert-Butoxycarbonyl-[2-(1-propoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}-[2S,3S]-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (268 mg, 0.4 mmol) using 4M-hydrogen chloride in dioxan (2 ml) to give the title compound as a white solid (93 mg). Found C, 51.04; H, 5.52; N, 15.24; C23H27F3N6O.2HCl.0.4H2O (540.64) requires C, 51.10; H, 5.56; N, 15.54%. Mass spectrum (thermospray +ve) m/e 461 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=O)[O:8][CH:7]2[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[S:22])[O:8][CH:7]2[CH3:12]
Reactant: CC1OC(=O)c2c(O)cccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CC1OC(=S)c2c(O)cccc21

Procedure:
3.9 g of 7-hydroxy-3-methyl-phthalide (see Examples 101 and 111) and 5.1 g of Lawesson reagent are heated in 20 ml of xylene for 4 hours at 140° C. Chromatographic filtration of the mixture on silica gel (eluant: ethyl acetate/n-hexane (1:9)] yields 7-hydroxy-3-methylisobenzofuran-1(3H)-thione, m.p. 39°-41° C.; IR spectrum (CHCl3): C=O 1624, 1604, 1368, 1330, 1304, 1165 cm-1 ; mass spectrum: 180 (M+ =100), 165(58), 137(24).