Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[O:4][C:5]([CH:19]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH3:20])(C(OCC2C=CC=CC=2)=O)[C:6](=[O:8])[N:7]=1.C(O)C>[C].[Pd].O1CCCC1>[CH3:31][N:2]([CH3:1])[C:3]1[O:4][CH:5]([CH:19]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH3:20])[C:6](=[O:8])[N:7]=1
Reactant: CC(c1c[nH]c2cc(F)ccc12)C1(C(=O)OCc2ccccc2)OC(N(C)C)=NC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(c1c[nH]c2cc(F)ccc12)C1OC(N(C)C)=NC1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
Benzyl 2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-4-oxo-2-oxazolin-5-carboxylate (500 mg) was dissolved into 15 ml of a solution of ethanol and tetrahydrofuran in a ration of 5:1. 10% palladium-carbon (170 mg) was added. The whole was subjected to hydrogenation under normal temperature and normal pressure for 1.5 hours. The whole was stirred at 80° C. under nitrogen atmosphere for 1 hour and then filtered to remove the catalyst. The filtrate was concentrated to give 2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-2-oxazolin-4-one (340 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[OH-].[NH4+:16]>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[CH2:4][S:5]([NH2:16])(=[O:7])=[O:6]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)Cc1c(Cl)cccc1Cl
Yield: 64 %

Procedure:
The 2,6-dichlorobenzylsulfonylchloride (27 g, 103.6 mmol) in ammonium hydroxide (270 ml) was stirred at room temperature for 3 hours. On acidification with cooled concentrated hydrochloric acid a precipitate separated and was filtered to give desired product (16 g, 64%) MS(EI) m/e 239 (M−).
Reaction SMILES: [NH2:1][C:2]1[C:10](I)=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:12])=[CH:4][CH:3]=1.[C:13](N)(=[S:15])[CH3:14].[O-2].[Ca+2].O>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][C:13]1[S:15][C:10]2[C:9]3[C:8](=[O:12])[CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(N)=S
Reactant: Nc1ccc2c(c1I)C(=O)CC2
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc3c(c2s1)C(=O)CC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
6-Amino-7-iodoindan-1-one (1.00 g, 3.66 mmol), thioacetamide (413 mg, 5.49 mmol), 1,1′-bis(diphenylphosphino)ferrocene (383 mg, 1.46 mmol), calcium oxide (411 mg, 7.32 mmol) and tris(dibenzylideneacetone)dipalladium(0) (335 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (12 mL), and the mixture was stirred at 60° C. for 1 hr. After allowing to cool to room temperature, water was added to the reaction solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=25/75→65/35), and then purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→40/60) to give the title compound (340 mg, yield 46%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13](C)[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N1CCC(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)C(C)C.[CH3:63][S:64](Cl)(=[O:66])=[O:65]>>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([S:64]([CH3:63])(=[O:66])=[O:65])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)CN1CCC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: Cl
Product: CC(C)CN1CCC(c2cn(S(C)(=O)=O)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 2, free base) and methanesulfonylchloride (commercially available). MS (m/e): 489.2 (MH+).
Reaction SMILES: C[S-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([Cl:13])[C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:16][CH2:15]1.O.Cl>CN(C=O)C>[Cl:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([Cl:13])[C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(Cl)c(N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(Cl)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(Cl)c(N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(Cl)c1
Temperature: 100 °C
Yield: 63.9 %

Procedure:
A suspension of 0.8 gram (0.011 mole) of sodium methanethiolate in 25 mL of DMF was stirred, and a solution of 1.8 grams (0.0044 mole) of 1,3-dichloro-5-methoxy-2-{4-[3-(trifluoromethyl)phenyl]piperazinyl}benzene in 40 mL of DMF was added. Upon completion of addition, the reaction mixture was heated to 100° C. where it stirred for two hours. After this time, the reaction mixture was cooled in an ice-water bath and 50 mL of water, followed by 25 mL of an aqueous solution of 10% hydrochloric acid, were added dropwise. The reaction mixture was then saturated with sodium chloride and extracted with two 50 mL portions of diethyl ether. The combined extracts were dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane, then 100% methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:15]1([C:13]([C:6]2[C:7]([CH3:12])=[N:8][C:9]3[C:4]([C:5]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:3][C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:11][CH:10]=3)=[O:14])[CH2:16][CH2:17]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C1CC1
Reactant: C1COCCN1
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccccc2)c1C(=O)C1CC1
Yield: 67 %

Procedure:
The title compound was prepared from [(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-cyclopropyl-methanone [example 55] and morpholine according to the procedure of example 51. Yield: 67%; MS: m/z=373 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:14][CH2:13]1)(=[O:11])=[O:10])#[N:2].C1C=C([O:42]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@@H:27]([CH2:29][NH+:30]([O-:42])[C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:16][CH2:17]1)(=[O:11])=[O:10])#[N:2]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(=O)(=O)c4ccccc4C#N)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(=O)(=O)c4ccccc4C#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-N-[[3-[4-[4-[(2-cyanophenyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (VIII-G, R1=COCH3, R9=2-cyanophenyl, X1=F, X2=H) (0.5 g) is suspended in 10 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.616 g) is added and the reaction mixture is stirred at room temperature for 2 hours. The reaction is concentrated and the resulting oil is chromatographed on silica gel using 7% methanol (saturated with ammonia) in chloroform as eluent to afford 0.33 g of the N-oxide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1([CH3:21])[CH2:20][O:19][CH2:18]1>CC#N>[CH3:16][C:17]1([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:20][O:19][CH2:18]1
Reactant: CC1(CBr)COC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(Cn2cc([N+](=O)[O-])cn2)COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
A mixture of 4-nitropyrazole (1.13 g, 10 mmol) and K2CO3 (3.4 g, 25 mmol) in MeCN (50 mL) was stirred at room temperature for 15 min prior to addition of 3-(bromomethyl)-3-methyloxetane (1.8 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 hr, filtered and the filter cake washed with MeCN. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) gradient to afford 1-((3-methyloxetan-3-yl)methyl)-4-nitro-1H-pyrazole as a colorless solid (1.43 g, 73%). A portion of this solid (206 mg, 1.04 mmol) dissolved in MeOH (20 mL) was treated with ammonium formate (260 mg, 4.13 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 80° C. for 1.5 hr, cooled, filtered through Celite® and the filtrate concentrated under reduced pressure to afford 1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-amine as a pale pink gum (160 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 6.97 (s, 1H), 4.66 (d, J=6.1 Hz, 2H), 4.37 (d, J=6.1 Hz, 2H), 4.19 (s, 2H), 2.91 (s, 2H), 1.23 (s, 3H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(O)CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5]([OH:14])=[N:4][CH:3]=[C:2]2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(O)ncc(N3CCOCC3)c2c1
Yield: 56.6 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.5 g, 1.968 mmol) and morpholine (0.429 g, 4.92 mmol) in ethylene glycol (2.5 ml) was added DIPEA (1.031 ml, 5.90 mmol). The reaction was irradiated in a microwave at 145° C. for 1.5 h. The reaction mixture was adsorbed on silica was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get desired compound (0.29 g, 53.8%) as solid. 1H NMR (400 MHz, CDCl3): δ ppm 10.98(s, 1H), 8.11 (s, 1H), 7.24-7.11 (m, 3H), 3.88 (s, 3H), 3.56-3.55 (m, 4H), 2.52-2.51 (m, 4H); MS: MS m/z 261 (M++1).
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:27])=[N:4][C:5](=[O:26])[N:6]([CH:25]=1)[C@@H:7]1[O:24][C@H:11]([CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:9]([OH:10])[CH2:8]1.[N-:28]=[N+:29]=[N-:30].[Li+]>CN(C=O)C>[I:1][C:2]1[C:3]([NH2:27])=[N:4][C:5](=[O:26])[N:6]([CH:25]=1)[C@@H:7]1[O:24][C@H:11]([CH2:12][N:28]=[N+:29]=[N-:30])[C@@H:9]([OH:10])[CH2:8]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(I)c(N)nc3=O)C[C@@H]2O)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Yield: 64.7 %

Procedure:
A mixture of the compound of Example 1 (2.80 g, 5.52 mmol) and lithium azide (0.41 g, 8.28 mmol) in 30 ml of DMF is heated to 75°-80° (oil bath) for 2 h. The solvent is evaporated to dryness under reduced pressure. The residue is coevaporated several times with ethanol and triturated with ether. The white solid is collected by filtration, washed with ice-cooled water, a small amount of ethanol and ether, and then dried under reduced pressure to afford 1.35 g (65%) of the desired product. An analytical sample is obtained by recrystallization from 95% ethanol; mp 185°-186° (dec); ir (KBr): 4.78 λ (azido).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:31]([C:30]3[CH:29]=[CH:28][C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:34][CH:33]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 74.9 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 4-morpholin-4-yl-benzaldehyde (24.9 mg, 0.130 mmol) were reacted to produce 45 mg (75%) of the title compound. mp: 283-284° C., 1H NMR (300 MHz, DMSO-d6): 12.97 (s, 1H), 8.22 (s, 1H), 8.00 (d, J=8 Hz, 2H), 7.93 (s, 1H), 7.65 (s, 1H), 7.11 (s, 1H), 7.03 (d, J=8 Hz, 2H), 6.98 (d, J=8 Hz, 1H), 6.36 (br s, 1H), 6.33 (br s, 1H), 5.27 (t, J=8 Hz, 1H), 3.77 (br s, 4H), 2.88 (s, 1H), 2.77 (s, 1H), 2.62 (d, J=7 Hz, 1H), 2.26 (br s, 4H), 1.39 (d, J=8 Hz, 1H). MS: 509, 511 (M+H), HPLC: 2.31 min (G method).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][CH:35]=1)=[O:5])C.[OH-].[Na+]>>[OH:5][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)(=[O:21])=[O:20])=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40](=[NH:41])[NH2:42])=[CH:38][CH:39]=1)=[O:3]
Reactant: CCOC(=O)CCCn1c(COc2ccc(C(=N)N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc21
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(OCc2nc3cc(NS(=O)(=O)c4cccc5cccnc45)ccc3n2CCCC(=O)O)cc1

Procedure:
Prepared analogously to Example 3 from 1-(3-ethoxycarbonylpropyl)-2-[(4-amidinophenyl)-oxymethyl]-5-(quinoline-8-sulphonylamino)-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 28 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 167B (0.186 g, 0.5 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants and preparative HPLC (C18 column and 55-70% MeCN/H2O with 0.05% AcOH) to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.072 g, 28%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.56 (m, 4H), 7.33-7.47 (m, 5H), 7.24 (d, 1H), 6.51 (s, 1H), 4.71 (m, 2H), 4.55 (m, 2H), 4.33 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.31 (s, 3H); LC-MS (ESI) m/z 635 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=O)[CH2:14][CH:13]2[C:31](OC)=[O:32])(=[O:11])=[O:10])=[CH:5][CH:4]=1>O1CCCC1.CO>[OH:32][CH2:31][CH:13]1[N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([CH2:23][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:14]1
Reactant: COC(=O)C1CN(C(=O)c2cccnc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(Cc3cccnc3)CC2CO)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
A mixture of 0.100 g (0.208 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate and 3 ml of borane-tetrahydroforan complex in tetrahydrofuran (1.0 M) was refluxed overnight. The solution was cooled to room temperature, diluted with methanol and the solvent removed. Methanol was added several times and, after each addition. the solvent was removed. To the residue was added 1N NaHCO3. The mixture was stirred for 45 minutes and then extracted with ethyl acetate. The extract was concentrated and then washed with H2O, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue chromatographed on thick layer silica gel plates with 10% methanol in ethyl acetate as solvent to give 60 mg of solid (RF 0.26). Crystallization from ethyl acetate gave 30 mg of white crystals. Anal. for C23H25N3O4S: Calc'd: C,62.8; H,5.7; N,9.6; S,7.3; Found: C,61.1; H,5.6; N,9.2; S,7.3; Mass spectrum (ES) 440.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:33])[CH:25]=2)[CH:16]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(Cc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 64.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-methylbenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.076 g; 0.218 mmol), m-tolylboronic acid (0.030 g; 0.223 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.047 g; 0.437 mmol), sodium iodide (0.066 g; 0.437 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.057 g (63%) of the title compound as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:18]([O:22][C:23]1[C:24]([CH:29]=O)=[N:25][CH:26]=[CH:27][N:28]=1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:18]([O:22][C:23]1[C:24]([CH2:29][N:15]2[CH2:14][CH2:13][CH:12]([C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[CH2:17][CH2:16]2)=[N:25][CH:26]=[CH:27][N:28]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: O=C(Cc1ccccc1F)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2F)CC1
Reaction time: 84 h
Yield: 75.7 %

Procedure:
After suspending 295 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride in 6 ml of dichloromethane, 247 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 364 mg of sodium triacetoxyborohydride were added while stirring on ice, and the stirring was continued for 3.5 days at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture to render it alkaline, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (334 mg, 76% yield).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[NH:10][CH:9]=1)=[O:7])C>O.CCO>[CH:14]([C:11]1[NH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[C:12]=1[CH3:13])=[O:15]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)c[nH]c1C=O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
KOH (5 g, 2 eq) was added to a suspension of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (8.13 g, 44.8 mmol) in water (100 mL) and EtOH (50 mL) with stirring. The mixture was heated to reflux for 2.5 hr, cooled to rt, concentrated to about ⅔ volume, diluted with water (300 mL) and acidified to pH=3 using 1N HCl. The white solid was collected by filtration and dried to afford 6 g (87%) of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid as a tan solid.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH3:17])=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=[N:13]2)=[CH:8][CH:7]=1.[C:21]1(C)C=CC=C[CH:22]=1>>[CH2:21]([O:19][C:18]([C:15]1[CH:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=2)[C:16]=1[CH3:17])=[O:20])[CH3:22]
Reactant: Cc1ccccc1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C

Procedure:
Toluene (40 ml) and thionyl chloride (8.0 ml) were added to 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (20.50 g) described in reference Example 13, stirred under reflux and the solvent was evaporated in vacuo. Pyridine (20 ml) and ethanol (40 ml) were added to the residue, and the mixture was stirred again under reflux and then the solvent was evaporated in vacuo. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting solid was washed with n-hexane to give 1-(4-bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (15.83 g).