Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:28])[CH:9]([OH:27])[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:16]=[C:15]([Cl:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O>[CH2:1]([C@:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:28])[C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[C:17]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:16]=[C:15]([Cl:25])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1cc(C(=O)NCC(O)[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(c1cc(C(=O)NCC(=O)[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a −20° C. solution of tert-butyl (1R)-1-benzyl-3-({2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinoyl}amino)-2-hydroxy-1-methylpropylcarbamate (0.400 g, 0.74 mmol) in 8 mL CH2Cl2/4 mL DMSO was added triethylamine (0.41 mL, 2.96 mmol). After 5 min, a solution of pyridine sulfur trioxide (0.471 g, 2.96 mmol) in 3 mL DMSO was added via cannula. After 16 h at ambient temperature, the reaction was quenched with brine (10 mL) and extracted with Et2O (15 mL). The aqueous layer was back extracted with Et2O (10 mL×2). The combined organics were washed with 10% aqueous sodium bisulfite (10 mL), and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase chromatography (20->70% EtOAc/hexanes) yielded 0.335 g (84%) of tert-butyl (1R)-1-benzyl-3-({2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinoyl}amino)-1-methyl-2-oxopropylcarbamate as a white solid. NMR (CDCl3, 400 MHz) 7.69 (d, J=1.01 Hz, 1H); 7.51 (d, J=0.92 Hz, 1H); 7.31 (m, 3H); 7.12 (m, 2H); 4.62 (m, 1H); 4.41 (m, 1H); 3.44 (s, 3H); 3.11 (s, 3H); 1.48 (s, 9H); 1.31 (s, 3H); LC/MS [M−C4H7]+=483.
Reaction SMILES: C([NH:4][C:5]1[C:10]([CH2:11][C:12]2[CH:21]=[C:20]([O:22][CH3:23])[C:15]([C:16](O)([CH3:18])[CH3:17])=[C:14]([O:24][CH3:25])[CH:13]=2)=[CH:9][N:8]=[C:7]([NH2:26])[N:6]=1)(=O)C.Cl.N>>[NH2:26][C:7]1[N:6]=[C:5]([NH2:4])[C:10]([CH2:11][C:12]2[CH:13]=[C:14]([O:24][CH3:25])[C:15]([C:16]([CH3:18])=[CH2:17])=[C:20]([O:22][CH3:23])[CH:21]=2)=[CH:9][N:8]=1
Reactant: COc1cc(Cc2cnc(N)nc2NC(C)=O)cc(OC)c1C(C)(C)O
Agent: Cl
Agent: N
Product: C=C(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC

Procedure:
A solution of 5.0 mg. of 4-[(4-acetylamino-2-amino-5-pyrimidyl)-methyl]-2,6-dimethoxy-α,α-dimethylbenzyl alcohol was warmed under reflux for 1 hour in 1 ml. of concentrated hydrochloric acid. After cooling, the mixture was adjusted to pH 10 with concentrated aqueous ammonia and extracted three times with 2 ml. of ethyl acetate each time. The extract was dried and evaporated. The residue yielded, after recrystallization from methanol, 3.2 mg. of 2,4-diamino-5-(4-isopropenyl-3,5-dimethoxybenzyl)-pyrimidine, having a melting point of 228°-229° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.[CH3:21][C:22]([CH3:24])=O>>[CH:22]([NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)([CH3:24])[CH3:21]
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Reactant: CC(C)=O
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NC(C)C)c1

Procedure:
Synthesized from 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (1.4 g) and acetone (1.5 ml) according to an analogous synthetic method to Example 38, the title compound (1.2 g) was obtained.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]#[N:28])[N:25]=1>>[C:27]([CH2:26][C:24]1[N:25]=[C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[S:22][CH:23]=1)#[N:28]
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Reactant: N#CCc1csc(N)n1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2nc(CC#N)cs2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using (2-Amino-thiazol-4-yl)-acetonitrile instead of 3-Chloroaniline to yield the final compound as a light yellow solid, MS (ISP): m/e=354.1 (M+H)+.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C(C)=CC=CC=1.[Na]>O>[N:6]1[CH:7]=[CH:8][C:3]([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:16])=[CH:4][CH:5]=1
Reactant: N#Cc1ccncc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a 500 mL RB flask were charged 4-cyanopyridine (10.4 g, 0.1 mole) and benzophenone (18.2 g, 0.1 mole). To this, xylene (250 mL) and sodium metal (5.0 g, 0.22 mole) cut into small pieces were added. The flask was heated slowly and refluxed under an inert atmosphere (e.g. nitrogen) with magnetic stirring for 3 hours. The color of the reaction mixture changed from clear to dark blue to dark brown during this time. The reaction mixture was cooled to room temperature and water was carefully added (150 mL). The solid product was filtered and washed with water and acetone. 4-Pyridyl diphenyl carbinol (18.3 g, 70% yield) was thus recovered with m.p. 238°-240° C.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(=[O:5])[CH3:4].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>CN(C=O)C>[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])(=[O:5])[CH3:4]
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1O
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To the suspension of 0.26 g of sodium hydride in anhydrous DMF, the soution of 1.36 g of 3-acetyl-2-(2-hydroxyphenyl)-benzothiazoline in 5 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 0.61 g of 3-dimethylaminopropyl chloride in 10 ml of anhydrous DMF is added. The reaction mixture is stirred for 2 hours at 80° C., and washed with n-hexane after cooling and poured into ice-water. The separated oil is extracted with ethyl acetate. The organic layer is washed with N--NaOH solution, water and saturated sodium chloride solution in the order named and dried over anhydrous magnesium sulfate. Ethy acetate is removed off in vacuo to give 1.0 g (56%) of the titled compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[CH:26]=[CH:25]2.C1(C)C=CC=CC=1.C(OC=C)=C>C1COCC1.Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.CC(C)=O>[N:32]1([C:30]([C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[C:20]([C:6](=[O:8])[CH3:7])[CH:21]=[CH:22][CH:23]=3)[N:28]=2)=[O:31])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(c1ccc2cccc(Br)c2n1)N1CCOCC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=COC=C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cccc2ccc(C(=O)N3CCOCC3)nc12
Temperature: 100 °C
Reaction time: 63 h
Yield: 92.3 %

Procedure:
A mixture of Pd(PPh3)4 (18 mg, 0.016 mmol), tributyl(1-ethoxyvinyl)stannane (0.12 mL, 0.34 mmol), (8-bromoquinolin-2-yl)(morpholino)methanone (Example 167a; 100 mg, 0.31 mmol), and toluene (1.5 mL) were stirred in a sealed 5 mL glass microwave tube under argon at 100° C. for 63 h. Formation of both the vinyl ether (M+1=313.1) and the methyl ketone (M+1=285.0) were detected by LCMS. The mixture was concentrated under reduced pressure, and the residue was adsorbed onto silica gel. Chromatographic purification (silica gel, 10-70% EtOAc in hexanes) afforded a mixture of the vinyl ether and the methyl ketone as a colorless oil. The material was dissolved in THF (3 mL), the solution was cooled to 0° C., 2 drops of 1N HCl were added and the solution was stirred at 0° C. for 5 min. EtOAc (25 mL) was added to the reaction mixture and the solution was washed successively with 1N NaOH (5 mL), water (10 mL) and brine (10 mL). The combined aq. washes were extracted with 25% IPA in CHCl3, and all organic layers were then combined, dried over MgSO4, filtered, and concentrated in vacuo to give 1-(2-(morpholine-4-carbonyl)quinolin-8-yl)ethanone (81.4 mg, 0.286 mmol, 92% yield) as a white film: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (d, J=8.6 Hz, 1H), 8.18-8.24 (m, 1H), 7.95 (dd, J=7.1, 1.3 Hz, 1H), 7.72-7.83 (m, 2H), 3.72 (s, 4H), 3.56 (d, J=4.7 Hz, 4H), 2.79 (s, 3H). m/z (ESI, +ve ion) 285.0 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([NH:34][C@H:35]([CH2:37]O)[CH3:36])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(Cl)Cl>[I:25][CH2:37][C@@H:35]([NH:34][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:36]
Reactant: II
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](CI)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
PS-triphenylphosphine (2.5 mmol/g, 1.3 g, 3.3 mmol) was suspended in methylene chloride (12 mL). Imidazole (225 mg, 3.3 mmol) was added and the mixture was cooled to 0° C. in an ice-water bath. To the cooled mixture was added iodine (838 mg, 3.3 mmol), and the resulting mixture was warmed to room temperature, stirred 10 minutes and recooled to 0° C. Boc-L-alaninol (463 mg, 2.64 mmol) in methylene chloride (3 mL) was added over several minutes. The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature and stirred 2 h. The mixture was filtered. The solids collected were washed thoroughly with ethyl acetate. The filtrate washed with dilute aqueous HCl (3%), sodium thiosulfate (1 M), saturated aqueous sodium bicarbonate and brine. The extracts were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude tert-butyl [(1S)-2-iodo-1-methylethyl]carbamate (xxvii) was obtained as a yellow oil and used without further purification. 1H NMR (300 MHz, CDCl3): δ 3.34-3.56 (m, 2H), 3.27 (dd, J=3.7, 9.8 Hz, 1H), 1.43 (s, 9H), 1.18 (d, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][CH:2]([CH2:14][Cl:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](O)=[O:12])=[N:9][CH:10]=1.S(Cl)(Cl)=O.C(Cl)(Cl)Cl.[NH3:24]>C1C=CC=CC=1>[Cl:1][CH:2]([CH2:14][Cl:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:24])=[O:12])=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(CCC(Cl)CCl)cn1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)c1ccc(CCC(Cl)CCl)cn1

Procedure:
10 g of 5-(3,4-dichlorobutyl)picolinic acid was added to the solution of thionyl chloride (30 ml) and chloroform (100 ml), and resulting solution was refluxed for fifteen minutes. The reaction mixture was evaporated in reduced pressure to obtain oily residue. This was dissolved in 100 ml of benzene and treated with 28% aqueous ammonia (50 ml) at 4° - 10°C with vigorous stirring for an hour. Benzene extract was evaporated in reduced pressure to give crude product as solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][CH:25]=3)[CH3:23])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:35]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]>>[CH2:35]([N:39]1[CH2:44][CH2:43][N:42]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:34])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH:22]([C:24]4[CH:29]=[CH:28][C:27]([S:30](=[O:32])(=[O:33])[NH2:31])=[CH:26][CH:25]=4)[CH3:23])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:41][CH2:40]1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN1CCNCC1
Reactant: CC(NS(=O)(=O)c1ccc(NC(=O)Nc2cccc(C#N)c2)cc1)c1ccc(S(N)(=O)=O)cc1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NC(C)c4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 8 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(1-(4-sulfamoylphenyl)ethyl)benzenesulfonamide following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[O:16])[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[S:9][C:10]([C:14](=[O:16])[CH3:15])=[C:11]([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: C1=CCCCC1
Reactant: CC(=O)c1sc(-c2ccc(I)cc2)nc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1sc(-c2ccc(C3=CCCCC3)cc2)nc1C
Temperature: 80 °C
Yield: 39 %

Procedure:
A solution of 4-iodophenylthiazole 4i (100 mg, 0.3 mmol) in dry DMF (5 mL) was charged with Pd(OAc)2 (5 mg), cyclohexene (1 mL) and triethylamine (0.5 mL). The reaction mixture was heated at 80° C. for 5 h. The reaction mixture was quenched with distilled water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated and dried over anhydrous Na2SO4. After evaporation of solvent under reduced pressure, the oily residue was collected and purified by silica gel flash chromatography, using hexane-ethyl acetate (9:1), to yield faint yellowish oil (35 mg, 39%). 1H NMR (CDCl3) δ 7.90 (d, J=8.1 Hz, 2 H), 7.29 (d, J=8.1 Hz, 2 H), 5.76 (m, 2 H), 2.80 (m, 1 H), 2.77 (s, 3 H), 2.55 (s, 3 H), 2.27-1.24 (m, 6 H); 13C NMR (CDCl3) δ 190.45, 169.54, 159.46, 150.94, 130.84, 130.63, 128.42, 127.60, 126.97, 126.33, 40.06, 32.98, 30.73, 29.40, 25.59, 18.45; CIMS m/z (rel intensity) 298 (MH+, 100); HRMS (EI), m/z 297.1189 M+, calcd for C18H19NOS 297.1187.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([OH:10])[CH:5]=[CH:4][C:3]=1[O:11][C:12](=[O:14])[CH3:13].Cl[CH2:16][C:17](=[O:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:17]([C:18]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:11][C:12]([CH3:13])=[O:14])=[C:2]([Cl:1])[C:7]=2[C:8]=1[NH2:9])(=[O:19])[CH3:16]
Reactant: CC(=O)CCl
Reactant: CC(=O)Oc1ccc(O)c(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Oc1ccc2oc(C(C)=O)c(N)c2c1Cl
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 107.8 %

Procedure:
To a solution of 7D (2.2 g, 10.4 mmol) in MeCN (20 mL) was added 1-chloro-propan-2-one (1.25 g, 13.52 mmol, 1.3 eq), followed by K2CO3 (1.868 g, 13.52 mmol, 1.3 eq). The mixture was stirred at 90° C. for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was quenched with water (100 mL) The white solids were precipitated out and collected by filtration and dried to give product 7E (3 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:23]=[C:22]([N:24]5[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)[CH:21]=[N:20][CH:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:5]1.Cl.O1CCOCC1>O1CCOCC1>[N:24]1([C:22]2[N:23]=[C:18]([N:17]3[C:11]4[CH:10]=[C:9]([C:7]5[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:39])([F:38])[F:1])[CH:8]=5)[N:14]=[CH:13][C:12]=4[CH:15]=[N:16]3)[CH:19]=[N:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)Cn1cc(-c2cc3c(cn2)cnn3-c2cncc(N3CCCNCC3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of tert-butyl 4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate (80 mg, 0.147 mmol) in 1,4-dioxane (6 mL) was added a solution of HCl/1,4-dioxane (3.8 M, 6 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give a crude product. The crude was purified by reverse phase preparative HPLC to afford 178 as a white solid (55 mg, 84%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.17 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.37 (d, J=6.0 Hz, 2H), 8.09 (s, 1H), 8.02 (s, 1H), 5.26 (Q, J=9.2 Hz, 2H), 3.86 (s, 2H), 3.81 (s, 2H), 3.01 (t, J=5.5 Hz, 2H), 2.76 (t, J=5.5 Hz, 2H), 1.89 (t, J=5.5 Hz, 2H). MS (ESI) m/z: 444 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:19][C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:21][N:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:19][C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[CH:21][N:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1ncc(-c2cccs2)o1
Product: c1csc(-c2cnc(COc3ccc(CCCn4ccnc4)cc3)o2)c1
Yield: 90 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 2-chloromethyl-5-(2-thienyl)oxazole to obtain 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-(2-thienyl)oxazole. The yield was 90%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 75-76° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][N:29]([CH3:40])[S:30]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH3:40])[S:30]([C:33]1[S:37][C:36]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])=[N:35][C:34]=1[CH3:39])(=[O:31])=[O:32]
Reactant: Cc1nc(N)sc1S(=O)(=O)N(C)CCO
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N(C)CCO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (example B.20) according to general procedure II.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11]CC2C=CC=CC=2)[C@H:9]([O:19]CC2C=CC=CC=2)[C@@H:8]([CH2:27][OH:28])[O:7][C@H:6]1[O:29][C@H:30]1[C@@H:63]([O:64]CC2C=CC=CC=2)[C@@H:62]([CH2:72][OH:73])[O:61][C@@H:32]([O:33][CH2:34][CH:35]([CH2:37][CH2:38][CH2:39][C@H:40]([C@@H:42]2[C@:59]3([CH3:60])[C@H:45]([C@H:46]4[C@H:56]([CH2:57][CH2:58]3)[C@:54]3([CH3:55])[CH:49]([CH2:50][CH2:51][CH2:52][CH2:53]3)[CH2:48][CH2:47]4)[CH2:44][CH2:43]2)[CH3:41])[CH3:36])[C@@H:31]1[O:74]CC1C=CC=CC=1)(=[O:3])[CH3:2].[H][H]>CO.O.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:19])[C@@H:8]([CH2:27][OH:28])[O:7][C@H:6]1[O:29][C@H:30]1[C@@H:63]([OH:64])[C@@H:62]([CH2:72][OH:73])[O:61][C@@H:32]([O:33][CH2:34][CH:35]([CH2:37][CH2:38][CH2:39][C@H:40]([C@@H:42]2[C@:59]3([CH3:60])[C@H:45]([C@H:46]4[C@H:56]([CH2:57][CH2:58]3)[C@:54]3([CH3:55])[CH:49]([CH2:50][CH2:51][CH2:52][CH2:53]3)[CH2:48][CH2:47]4)[CH2:44][CH2:43]2)[CH3:41])[CH3:36])[C@@H:31]1[OH:74])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N[C@H]1[C@H](O[C@H]2[C@@H](OCc3ccccc3)[C@@H](CO)O[C@@H](OCC(C)CCC[C@@H](C)[C@H]3CC[C@H]4[C@@H]5CCC6CCCC[C@]6(C)[C@H]5CC[C@]34C)[C@@H]2OCc2ccccc2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N[C@H]1[C@H](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](OCC(C)CCC[C@@H](C)[C@H]3CC[C@H]4[C@@H]5CCC6CCCC[C@]6(C)[C@H]5CC[C@]34C)[C@@H]2O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 80 %

Procedure:
Compound 30 (230 mg, 0.209 mmol) was dissolved in a mixture of methanol, water and ethyl acetate (4:1:1, 25 mL), and palladium hydroxide/carbon (230 mg) was added thereto. Inside of the reaction system was replaced with hydrogen gas, and catalytic reduction was performed at room temperature for 20 hours. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified with a column of Sephadex LH-20 (CHCl3:MeOH=1:1) to obtain Compound 33 (126.1 mg, 81.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1Br.C(=O)([O-])[O-].[Na+].[Na+].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C=O)cc1Br
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C=O)cc1-c1cccs1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.21 mmol) was added to a solution of 4-methoxy-3-bromobenzaldehyde (1.5 g, 6.98 mmol) in toluene (15 mL) and ethanol (15 mL), followed by a 2 M aqueous solution of sodium carbonate (14 mL, 28 mmol). To this mixture was added thiophene-2-boronic acid (0.98 g, 7.68 mmol), and the mixture was heated to reflux. After 3 hours, the reaction was partitioned between water (100 mL) and ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL), dried with magnesium sulfate and concentrated. Chromatography (silica, 20% ethyl acetate/hexanes) afforded 1.3 g (87%) of 4-methoxy-3-thiophen-2-yl-benzaldehyde as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCCC(CC(=O)OCC)n1ccc2cc(N)ccc21
Yield: 78.1 %

Procedure:
A mixture of 3-(5-nitro-indol-1-yl)-hexanoic acid ethyl ester (1.49 g, 4.9 mmol), and 10% palladium on activated carbon (149 mg) in ethanol (15 mL) was hydrogenated in a hydrogen balloon for 2 days. The mixture was filtered through Celite, and the Celite was washed with methanol. The filtrate and washing were combined, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (20, 30%) to afford the title compound (1.05 g, 78% yield) as dark brown oil. 1H NMR (CDCl3) δ 7.22 (d, 1H, J=8.7 Hz), 7.05 (d, 1H, J=3.2 Hz), 6.90 (d, 1H, J=2.3 Hz), 6.66 (dd, 1H, J=2.2, 8.7 Hz), 6.33 (d, 1H, J=3.2 Hz), 4.78-4.73 (m, 1H), 4.02-3.96 (m, 2H), 3.47 (bs, 2H), 2.87-2.74 (m, 2H), 1.94-1.87 (m, 1H), 1.84-1.77 (m, 1H), 1.27-1.09 (m, 2H), 1.08 (t, 3H, J=7.1 Hz), 0.85 (t, 3H, J=7.3 Hz).