Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[H-].[Na+].[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:4]([O:8][CH2:9][CH2:10][O:11][C:25]2[N:26]=[CH:27][C:22]([Br:21])=[CH:23][N:24]=2)[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(N)ncnc2OCCO)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(N)ncnc2OCCOc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of 2-{6-amino-5-(4-methylphenyl)pyrimidin-4-yloxy}-ethanol (7.54 g)in tetrahydrofuran (150 ml) is added sodium hydride (60% dispersion, 1.47 g), and thereto is added 5-bromo-2-chloropyrimidine (7.73 g), and the mixture is stirred at room temperature overnight. To the reaction solution is added a saturated aqueous ammonium chloride solution, and the mixture is evaporated under reduced pressure to remove the solvent. The precipitated crystals are collected by filtration, washed, and dried. The crude crystals are purified by silica gel column chromatography (solvent; chloroform: methanol=100:1~80:1), and recrystallized from tetrahydrofuran-diethyl ether to give 4-amino-6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]-5-(4-methyl-phenyl)pyrimidine (11.27 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH2:8]([O:10][C:11]1[N:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]1[N:16]=[CH:15][C:14]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:13][CH:12]=1)[CH3:9]
Reactant: CCOc1ccc(O)cn1
Reactant: O=C1NCC[C@@H]1O
Solvent: C1CCOC1
Product: CCOc1ccc(O[C@@H]2CCNC2=O)cn1

Procedure:
A mixture of (S)-3-hydroxy-pyrrolidin-2-one (8.07 g), 6-ethoxypyridin-3-ol (11.0 g) and THF (100 mL) was purged with argon. Triphenylphosphine (20.7 g) was added followed by slow addition of DIAD (16.0 g). After 2 hours the mixture was concentrated and the residue purified by SGC (eluent: EA) to provide the subtitle compound. MS ESI+: m/z=223 [M+H]+.
Reaction SMILES: O[CH:2]([CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[CH:2](=[C:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(O)C1CCCC1=O
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCC=C1CCCC1=O
Yield: 86.4 %

Procedure:
In a 300 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-(1-hydroxyheptyl)cyclopentanone (70 g) synthesized in Reference Example 3, oxalic acid (0.7 g) and toluene (140 ml), and the whole was refluxed to allow dehydration to proceed. The formed water was removed and the reaction was continued until water was not formed any more (about 2.5 hours). The reaction mixture was washed with water and the layers were separated from each other. Further, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover toluene and unreacted cyclopentanone, whereby a crude product (63 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 55 g of 2-heptylidenecyclopentanone (boiling point: 56° C./400 Pa; GC purity: 98.5%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=[O:17])[CH2:12][CH2:11]2)=[C:5]([C:23](=[O:26])[CH2:24][CH3:25])[CH:4]=1.CCN(C(C)C)C(C)C.Cl.[C:37]([N:41]1[CH2:45][C@@H:44]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[F:53])[C@H:43](C(O)=O)[CH2:42]1)([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.C(Cl)Cl.O>[C:37]([N:41]1[CH2:45][C@@H:44]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[F:53])[C@H:43]([C:16]([N:13]2[CH2:12][CH2:11][CH:10]([C:6]3[CH:7]=[C:8]([CH3:9])[C:3]([CH3:2])=[CH:4][C:5]=3[C:23](=[O:26])[CH2:24][CH3:25])[CH2:15][CH2:14]2)=[O:17])[CH2:42]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Reactant: CCC(=O)c1cc(C)c(C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)c1cc(C)c(C)cc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h

Procedure:
A saturated solution of hydrogen chloride in EtOAc (10 mL) was added to a solution of 85 (1.15 g, 3.33 mmol) in DCM (5.0 mL) at ambient temperature. After 30 min the volatiles were evaporated in vacuo. The above residue was resuspended in DCM (10 mL) and to this stirred solution was added DIEA (1.73 mL, 9.9 mmol), (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid 80 (1.06 g, 3.3 mmol), and HATU (1.39 g, 3.6 mmol). After approximately 18 h, the reaction mixture was poured into water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-20% methanol [containing 10% v/v ammonium hydroxide]/DCM as eluent) afforded 86 as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:19]([NH:21][C@H:22]([C:24]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=[O:36])[C:27]5=[C:37]([CH3:40])[CH:38]=[CH:39][N:26]5[N:25]=4)[CH3:23])=[N:18][CH:17]=[N:16][C:15]=3[N:14](COCC[Si](C)(C)C)[CH:13]=2)[CH:7]=1)(=[O:5])=[O:4].FC(F)(F)C(O)=O.N>>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:19]([NH:21][C@H:22]([C:24]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=[O:36])[C:27]5=[C:37]([CH3:40])[CH:38]=[CH:39][N:26]5[N:25]=4)[CH3:23])=[N:18][CH:17]=[N:16][C:15]=3[NH:14][CH:13]=2)[CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1cccc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 76.6 %

Procedure:
(S)—N-Methyl-3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzenesulfonamide (76 mg, 0.08 mmol) was treated with trifluoroacetic acid (1.52 ml, 18.73 mmol) and a solution of ammonia (7N in methanol, 1.52 ml, 10.64 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 34 mg (71% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[C:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cn1cccc1CCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)Cc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)n1C

Procedure:
Prepared analogously to Example 28 from 2-(2-(4-chlorobenzenesulphonylamino)-ethyl)-1-methylpyrrole and ethyl diazoacetate.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29]2[CH:30]=[C:31]([NH2:34])[NH:32][N:33]=2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29]2[CH:30]=[C:31]([NH:34][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:32][N:33]=2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1oc(C(C)(C)C)cc1-c1cc(N)[nH]n1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1-c1cc(NC=C2C(=O)Nc3ccccc32)[nH]n1

Procedure:
The named compound is prepared by substituting 5-(5-tert-butyl-2-methyl-furan-3-yl)-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2987 gms. of 5-(5-tert-butyl-2-methyl-furan-3-yl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C[S+](C)C1C=CC(O[C:21](=[O:35])[C@H:22]([CH3:34])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=CC=1.[NH2:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:35])[CH3:34])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([S+](C)C)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In 50 ml of chloroform was dissolved 4.14 g of benzyloxycarbonylalanine p-dimethylsulfoniophenyl ester p-toluenesulfonate, and 20 ml of an aqueous solution of 0.91 g of valine and 1.1 ml of triethylamine was dropwise added thereto under stirring at room temperature. The reaction mixture was stirred for 8 hours at room temperature and then separated. The chloroform layer was washed with water, dried, and concentrated under reduced pressure, and ether was added to the residue to afford white crystals.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:18](=[O:19])[C:14]3([CH2:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]OS(C)(=O)=O)=[CH:22][CH:21]=3)[C:12]2=[S:32])=[CH:7][C:6]=1[C:33]([F:36])([F:35])[F:34])#[N:4]>C1COCC1>[CH3:1][NH:2][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:13]2[C:12](=[S:32])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[C:6]([C:33]([F:36])([F:34])[F:35])[CH:7]=3)[C:18](=[O:19])[C:14]32[CH2:17][CH2:16][CH2:15]3)=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: -78 °C
Yield: 82 %

Procedure:
Methylamine (0.5 ml) was bubbled into a mixture of Methanesulfonic acid 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]phenylmethyl ester (50a) (0.059 g, 0.115 mmol) in THF (3 ml) cooled to −78° C. After 1 hour of reaction at −78° C., the mixture was concentrated and chromatographed (dichloromethane:acetone, 95:5; methanol) to yield 4-[5-(4-methylaminomethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-7-yl]-2-trifluoromethylbenzonitrile (50b) [RD155] (0.042 g, 0.095 mmol, 82%), the structure of which is illustrated in Formula 23, as a white powder.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].C1(C)C=CC([O:23][C:24]([C:26]2[C:34]3[C:29](=[CH:30][C:31]([Cl:43])=[C:32]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH:33]=3)[NH:28][N:27]=2)=O)=CC=1>C1COCC1>[Cl:43][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:24]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[O:23])=[N:27][NH:28]2)=[CH:33][C:32]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1
Reactant: COc1ccc(-c2cc3c(C(=O)Oc4ccc(C)cc4)n[nH]c3cc2Cl)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c(C(=O)NS(=O)(=O)c4ccccc4)n[nH]c3cc2Cl)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 3.1 %

Procedure:
A mixture of benzenesulfonamide (25.6 mg, 0.163 mmol) and potassium tert-butoxide (22.0 mg, 0.196 mmol) in THF (10 mL) was stirred for 10 minutes, and treated with 6-chloro-5-(4-methoxyphenyl)-1H-indazole-3-carboxylic acid p-tolyl ester (64 mg, 0.16 mmol). The reaction mixture was heated to 65° C. for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (5 mL) and EtOAc (5 mL), and the layers were separated. The organic layer was concentrated in vacuo and the crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 60:40 A:B linear to 30:70 A:B in 8.5 min to 100% B to 9.0 min, hold at 100% B from 9.0 to 10.0 min. Flow: 25 mL/min) to give the title compound (2.2 mg, 3% yield). MS (ES+) 442.0 (M+1)+. Retention time=3.29 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [Li]CCCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][CH2:20][O:21][C:22](/[CH:24]=[C:25](/[CH2:27]P(OCC)(OCC)=O)\[CH3:26])=[O:23].[Si:36]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][C:50]1[C:51](/[C:64](/[CH3:68])=[CH:65]\[CH:66]=O)=[CH:52][C:53]2[C:54]([CH3:63])([CH3:62])[CH2:55][CH2:56][C:57]([CH3:61])([CH3:60])[C:58]=2[CH:59]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>C1COCC1.C(OCC)(=O)C.O.CN1CCCN(C)C1=O>[Si:36]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:49][C:50]1[C:51](/[C:64](/[CH3:68])=[CH:65]\[CH:66]=[CH:27]\[C:25](\[CH3:26])=[CH:24]\[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[CH:52][C:53]2[C:54]([CH3:63])([CH3:62])[CH2:55][CH2:56][C:57]([CH3:61])([CH3:60])[C:58]=2[CH:59]=1)([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: C/C(=C/C=O)c1cc2c(cc1OCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C=C(/C)c1cc2c(cc1OCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)CCC2(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A 2.5M solution of BuLi in hexane (1.12 mmol) was added dropwise to a solution of diisopropylamine (387 μl) in a 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)/THF (10 ml/10 ml) mixture at -20° C. The mixture was stirred for 30 min at -20° C., and triethyl 3-methyl-4-phosphonocrotonate (0.68 ml) was then added. The mixture was stirred for 1 h at -20° C. and was added to a solution of (Z)-3-{3-[5-(tert-butyldimethylsilyloxy)pentyloxy]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl}-2-butenal (1.1 g, 2.3 mmol) in THF (5 ml). The reaction medium was permitted to warm to room temperature and was then treated with ethyl acetate/water. After settling, the organic phase was separated and washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C. The desired compound was purified by flash chromatography on a silica column.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:18])=O.[N+](C1C([N+]([O-])=O)=C(C=CC=1)C(O)=O)([O-])=O.Cl>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([Cl:18])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(O)c1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 90 %

Procedure:
3,5 dinitrobenzoic acid and ethyl acetate were placed in a reaction vessel. While thionyl chloride with some drops of DMF (about double as many moles as dinitrobenzoic acid) was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and was poured into hexane and then the precipitated solid was separated by filtration. 3,5-dinitrobenzoic chloride was obtained in a 90% yield.
Reaction SMILES: O1CCCC1.[S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([S:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:19]([CH3:28])=[CH:18][C:17]=1[CH3:29])C#N.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.CCCCCC>[F:30][C:31]([F:33])([F:32])[S:6][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([S:22][CH2:23][C:24]([F:27])([F:25])[F:26])[C:19]([CH3:28])=[CH:18][C:17]=1[CH3:29]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCSC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCSC(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To 100 ml of tetrahydrofuran were added 1.37 g (3.63 mmol) of 6-thiocyanatohexyl-[2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenyl]ether and 1.29 g (9.07 mmol) of trifluoromethyltrimethylsilane. Thereto was added 0.4 ml (0.4 mmol) of tetrahydrofuran solution of tetra-n-butylammonium fluoride (1 mol/liter) at 0° C., and the mixture was stirred for 4 hours at 0° C. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=20:1), to obtain 1.36 g (yield: 89%) of an intended product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:28][CH3:29])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:28]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:24][CH:25]([CH3:27])[CH3:26])[CH:16]=2)[C:21]([C:22]#[N:23])=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([N:6]2[CH2:2][CH2:3][O:4][C:5]2=[O:30])=[CH:8][CH:9]=1)[CH3:29]
Reactant: CCn1c(-c2ccc(NC(=O)OCCCl)cc2)c(C#N)c2ccc(OC(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc(N3CCOC3=O)cc2)c(C#N)c2ccc(OC(C)C)cc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of [4-(3-cyano-1-ethyl-6-isopropoxy-1H-indol-2-yl)-phenyl]-carbamic acid 2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) is added aqueous K2CO3 (10 mg) and then stirred at 50° C. for 18 h. The reaction mixture is poured into cold water and the precipitate collected by filtration and washed with hexane and dried in vacuo to afford the title compound (21 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18](F)(F)F)[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>>[CH2:26]([N:10]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:17]2[C:12]([C:13]([CH3:18])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Yield: 5 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and allylbromide (0.086 mL, 1.0 mmol) to give the title compound (0.007 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:10][N:11]([C:13]3[C:18]([CH3:19])=[CH:17][C:16](=[O:20])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:10][N:11]([C:13]3[CH:18]([CH3:19])[CH2:17][C:16](=[O:20])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(=O)[nH]nc1-n1cc(-c2ccnc(N)c2)c(-c2ccc(F)cc2)n1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: CC1CC(=O)NN=C1n1cc(-c2ccnc(N)c2)c(-c2ccc(F)cc2)n1
Yield: 47 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 100 mg (0.28 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,6-dihydro-4-methyl-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 31-2) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 48.0 mg of the title compound as a white powder. (Yield: 48%)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[CH2:38]([O:45][C:46](Cl)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH2:38]([O:45][C:46]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)CC1
Reaction time: 3 h

Procedure:
A solution of 1-benzyl-4-[3-(1-naphthylsulfonylmethyl)-4-nitrophenoxy]-piperidine (4.7 g, 9.1 mmol) and benzylchloroformate (6.0 mL, 42 mmol) in benzene was heated at reflux temperature, under nitrogen, for 3 hours, cooled to ambient temperatures, poured into 2.5 N sodium hydroxide and extracted with ethyl acetate. The extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 30-50% ethyl acetate in hexane to afford 4-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-piperidine-1-carboxylic acid benzyl ester as a buff foam/amber gum, 3.9 g, 76%); Mass spectrum (+EI, [M+H]+) m/z 561. 1HNMR (500 MHz, DMSO-d6): δ8.44-8.46 (m, 1H), 8.30 (d, 1H, J=8.17 Hz), 8.07-8.10 (m, 1H), 7.94-7.99 (m, 2H), 7.61-7.68 (m, 3H), 7.27-7.37 (m, 5H), 7.09 (dd, 1H, J=9.15 Hz and 2.81 Hz), 6.72 (d, 1H, J=2.81 Hz), 5.23 (s, 2H), 5.05 (s, 2H), 4.36-4.40 (m, 1H), 3.58-3.61 (m, 2H), 3.10-3.20 (m, 2H), 1.70-1.74 (m, 2H), 1.34-1.42 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[Br:61][C:62]1[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=1>C1COCC1.CN(C=O)C>[Br:61][C:62]1[CH:68]=[CH:67][C:65]([NH:66][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:26])=[N:13][C:12]=3[CH:14]=2)=[O:25])=[CH:64][CH:63]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Br)cc3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 10.3 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.070 g, 0.177 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.157 g, 0.355 mmol), N-methyl morpholine (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and 4-bromo aniline (0.092 g, 0.531 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.23 (s, 3H), 1.57 (s, 3H), 3.06 (s, 2H), 7.24 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 8.44 (s, 2H), 9.72 (s, 1H), 10.98 (s, 1H), 11.52 (s, 1H); MS [M−H]−: 546.22.