Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[C:8]([C:9]2[N:10]([C:25]#[N:26])[C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([CH3:27])[S:6][N:5]=1>CO>[CH3:3][C:4]1[C:8]([C:9]2[N:10]([C:25](=[N:1][OH:2])[NH2:26])[C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([CH3:27])[S:6][N:5]=1
Reactant: NO
Reactant: Cc1nsc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C#N
Solvent: CO
Product: Cc1nsc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C(N)=NO
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.33 mL, 5.21 mmol) was added to 2-(3,5-dimethylisothiazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile (18 mg, 0.05 mmol) in MeOH (2 mL) and the reaction was stirred at 130° C. for 20 min in the microwave. The mixture was purified by preparative HPLC to give E24 2-(3,5-dimethylisothiazol-4-yl)-N′-hydroxy-3-(4-hydroxyphenyl)-1H-indole-1-carboximidamide (7.0 mg, 35%); ES/MS m/z 379.11 (M+H), 377.14 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.70 (dd, 1H, J=7.9, 1.0 Hz), 7.59 (dd, 1H, J=9.0, 0.9 Hz), 7.29 (m, 1H), 7.20 (m, 1H), 7.09 (m, 2H), 6.81 (m, 2H), 2.30 (s, 3H) and 2.16 (s, 3H) and E25 2-(3,5-dimethylisothiazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carboxamide (5 mg, 26%), ES/MS m/z 364.11 (M+H), 362.14 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.12 (d, 1H, J=8.4 Hz), 7.67 (d, 1H, J=7.9 Hz), 7.36 (m, 1H), 7.26 (m, 1H), 7.05 (m, 2H), 6.83 (m, 2H) and 2.21 (s, 6H). For each of the title compounds, identification by 1H-NMR showed that the amide oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:25])[N:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CC(O)=O>[NH2:18][C:14]1[CH:13]=[C:12]([CH:6]2[N:5]([C:21]([O:23][CH3:24])=[O:22])[C:4](=[O:25])[NH:3][C:2]([CH3:1])=[C:7]2[C:8]([O:10][CH3:11])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)OC)C1c1cccc(N)c1
Yield: 97 %

Procedure:
The title compound was prepared from the compound of Example 7 according to the method described in Example 2 using AcOH as solvent. A white solid was obtained (97% yield): mp 190°-193° C.; 1H NMR (CDCl3) δ 7.65 (s, 1 H), 7.05 (t, 1 H, J=7.8 Hz), 6.69 (d, 1 H, J=7.8 Hz), 6.64 (s, 1 H), 6.57 (d, 1 H, J=7.8 Hz), 6.30 (s, 1 H), 3.86 (s, 3 H), 3.74 (s, 3 H), 2.36 (s, 3 H); 13C NMR (CDCl3) δ 165.6, 153.7, 150.1, 146.6, 145.7, 140.6, 129.6, 116.6, 114.9, 113.0, 105.0, 56.0, 54.3, 51.6, 18.1.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.N#N.[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[Si:28]([C:20]1[C:19]([F:23])=[CH:18][N:17]=[C:16]([F:15])[C:21]=1[F:22])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1cnc(F)c(F)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
n-BuLi (41.09 mL of 1.6 M, 65.75 mmol) was added dropwise to a solution of diisopropylamine (6.919 g, 9.583 mL, 68.38 mmol) in THF (130 mL), cooled to −5° C. (under N2). After stirring for 15 min, the reaction mixture was cooled down to −78° C. 2,3,5-Trifluoropyridine (7 g, 52.60 mmol) was added dropwise to the reaction mixture which was stirred for 45 min. A solution of tert-butyl-chloro-dimethyl-silane (10.31 g, 68.38 mmol) in THF (15 mL) was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours. It was quenched with a saturated ammonium chloride aqueous solution (˜50 ml). The reaction mixture was partitioned between ethyl acetate and a saturated sodium bicarbonate aqueous solution. The aqueous was extracted with ethyl acetate twice. The combined organics were washed with brine. The organic was dried over magnesium sulfate and concentrated in vacuo after filtration. The crude mixture was purified on silica gel, eluting with petrol ether/ethyl acetate 0 to 20% to afford the title compound as a pale yellow solid (11.8 g, 90%). 1H NMR (CDCl3) 0.34 (6H, s), 0.87 (9H, s), 7.71 (1H, s).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:15][N+:16]([O-:18])=[O:17])=[O:8])=O>ClCCl.CO>[OH:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:15][N+:16]([O-:18])=[O:17])=[O:8]
Reactant: O=COCCOC(=O)N1CCCSC1=C[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: O=C(OCCO)N1CCCSC1=C[N+](=O)[O-]
Yield: 61.2 %

Procedure:
The compound of Example 3 (2 g) was passed down a column of neutral alumina (200 g) using a dichloro methane/methanol mixture (95/5, v/v) as eluent at a flow rate of approximately 35 ml per minute. The eluted material was concentrated and purified by column chromatography on silica to afford the title compound (1.1 g) and recovered starting material (600 g). Melting point of the product was 59°-62° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](CS([O-])(=O)=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:21][CH:20]=1
Reactant: COc1cc(CS(=O)(=O)[O-])cc(OC)c1OC
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1cc(Nc2ccc(F)cc2)cc(OC)c1OC
Temperature: 110 °C
Yield: 86.6 %

Procedure:
Following general procedure A, a mixture of 3,4,5-trimethoxyphenylmethanesulfonate (131 mg, 0.5 mmol), 4-fluoroaniline (57 μL, 0.6 mmol), K2CO3 (97 mg, 0.7 mmol), 10 (4 mg, 1 mol %), 1 (2.5 mg, 1 mol %), and t-BuOH (6 mL) was heated to 110° C. for 16 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 5-40% EtOAc/hexanes) to provide the title compound as a yellow oil (120 mg, 87%). 1H NMR (300 MHz, CDCl3) δ: 6.99 (m, 4H), 6.22 (s, 2H), 5.57 (s, 1H), 3.80 (s, 3H), 3.78 (s, 6H) ppm. 13C NMR (75 MHz, CDCl3) δ: 159.7, 156.5, 154.1, 140.5, 139.6, 132.5, 120.4, 120.3, 116.4, 116.1, 95.2, 61.3, 56.2 ppm. IR (neat, cm−1): 3360, 2937, 1597, 1499, 1454, 1216, 1129, 1007, 785. Anal. Calcd. for C15H16FNO3: C, 64.97; H, 5.82. Found: C, 65.24; H, 6.00.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.C(OC([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:41][C:38]4[CH:39]=[CH:40][C:35]([CH2:34][N:31]5[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]5)=[CH:36][N:37]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]2[O:15][CH:14]=[N:13][CH:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Clc1ncc2cc(-c3cnco3)n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)nc2)CC1
Product: c1ncc(-c2cc3cnc(Nc4ccc(CN5CCNCC5)cn4)nc3n2C2CCCC2)o1
Yield: 15 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-6-oxazol-5-y-l-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.346 mmol) and 4-(6-amino-pyridin-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (106 mg, 0.363 mmol), followed by deprotection using General Procedure A to give (7-cyclopentyl-6-oxazol-5-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(5-piperazin-1-ylmethyl-pyridin-2-yl)-amine (23 mg, 15%). MS (ESI) m/z 445.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]2[CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[C:4]([C:3]1[C:2]([F:1])=[C:9]([CH:10]([OH:11])[CH2:12][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]2[CH2:27][OH:28])[CH:8]=[CH:7][C:6]=1[F:13])#[N:5]
Reactant: N#Cc1c(F)ccc(C2CO2)c1F
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2F)[C@H](CO)C1
Temperature: 150 °C

Procedure:
2,6-Difluoro-3-(oxiran-2-yl)benzonitrile (1.50 g, 8.28 mmol) and (S)-4-N—BOC-2-hydroxymethylpiperazine (2.40 g, 11.1 mmol) were suspended in ethanol (15 mL) then heated in a microwave apparatus for 30 min at 150° C. The reaction mixture was cooled and evaporated dryness. The residue was purified by chromatography through a 120 g Redi-sep column eluting with 5% MeOH/95% EtOAc to yield the title compound LC-MS: M+1=398.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])=O.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[CH3:1][NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1NC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CNc1cc([N+](=O)[O-])ccc1OC
Temperature: 0 °C

Procedure:
To a 0.5M solution of 2-formamido-4-nitroanisole (745 mg, 3.8 mmol) in dioxane was added sodium borohydride (722 mg, 19 mmol) followed by dropwise addition of glacial acetic acid (1.09 mL, 19 mmol). The reaction mixture was refluxed for 40 minutes, then cooled to 0° C. and quenched slowly with MeOH. Excess MeOH was then added and the solution was concentrated under vacuum to yield 2-methylamino-4-nitroanisole. The crude product was dissolved in anhydrous MeOH (20 mL) and Pd/C (795 mg, 0.76 mmol) was added followed by bubbling hydrogen gas through the solution for 1 minute. The reaction mixture was then stirred for 1.5 h under 1 atmosphere of hydrogen. The reaction mixture was filtered through a pad of Celite and the filter pad was washed with MeOH (40 mL). To the combined filtrate and wash was added pentafluorophenylsulfonyl chloride (282 mL, 0.26 mmol). After stirring for 30 min the reaction mixture was concentrated under vacuum and purified by column chromatography (10-25% EtOAc in hexane) to yield 153 mg (21% for three steps) of the title compound as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ10.7 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.3 (dd, J=8.3, 2.5 Hz, 1H), 6.22 (d, J=2.2 Hz, 1H), 5.18 (bs, 1H), 3.7 (s, 3H), 2.6 (d, J=3 Hz, 3H). MS(EI): m/z 785 (35, 2M+Na−2H), 382 (20, M+), 381 (100, M−H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:26]1[CH:25]=[C:24]([C:23]2[CH2:22][C:21](=[O:37])[NH:20][C:9]3[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=3[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(OCC(F)(F)F)ccc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M52) (380 mg, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (201 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=O)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[S:26])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C1CCCC1C(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COc1ccc2c(c1)C1CCCC1C(=S)N2
Yield: 70.7 %

Procedure:
Analogously to Example 4, 8-methoxy-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (8 mg, 0.37 mmol) is reacted with Lawesson's reagent (404 mg, 1.0 mmol) to form 61 mg (71%) of product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:14]([NH:16][NH2:17])=O>C(O)CCC>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:14]=[N:16][N:17]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: c1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A 10 g. portion of 3-chloro-6-phenylpyridazine (Chem. Abs., 44, 5616i), 6.6 g. of formylhydrazine and 100 ml. of n-butanol are refluxed for 48 hours. The reaction mixture is cooled in an ice bath. The resulting solid is filtered, washed with petroleum ether and water and air dried giving 6-phenyl-1,2,4-triazolo[4,3-b]pyridazine as tan crystals, m.p. 138°-139° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:8]=[C:9]([S:13][CH3:14])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[N:10]=1
Reactant: CCOC(=O)C1=C(C)NC(SC)=NC1c1cccc(OC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc(SC)nc1-c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl-2-methylthio-4-(3-methoxyphenyl)-6-methyl-1,4-dihydro-pyrimidine-5-carboxylate (example 24a, 7.65 g) was dissolved in a mixture of toluene (200 ml) and CH2Cl2 (100 ml). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5.45 g) was added and the reaction mixture was stirred at room temperature for 15 min. 0.2M aq. NaOH (250 ml) was added. The organic layer was separated, washed with H2O (2*250 ml) and sat. aq. NaCl (2*250 ml), dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc=4/1 (v/v) as eluent.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[I:25]CCI.[Cl-].[NH4+]>O1CCCC1>[I:25][C:10]1[N:5]2[N:4]=[C:3]([S:2][CH3:1])[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1nn2ccccc2c1NC(=O)OC(C)(C)C
Reactant: ICCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (21.6 g) dissolved in tetrahydrofuran (1 L) was n-butyllithium (1.6M hexane solution; 130 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. A solution of 1,2-diiodoethane (24 g) in tetrahydrofuran (50 mL) was added to the obtained reaction mixture, and stirring was continued for 1 hour. After adding saturated aqueous ammonium chloride to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the organic extract was washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (21.5 g) was obtained as yellow crystals from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1cc(Br)c2c(c1)CC(CO)O2
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(C)C)cc(Br)c3O2)cc1
Yield: 97.1 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCCC1.C(O)C.[H][H].[C].[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C(=O)N(C)C)c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ccc(N)c(C(=O)N(C)C)c2)CC1

Procedure:
1-(3-Dimethylcarbamoyl-4-nitrophenyl)-piperidine-4-carboxylic acid ethyl ester (1.578 g) was dissolved in tetrahydrofuran (5 mL) and ethanol (5 mL). After addition of 7.5% (w/w) palladium-carbon (0.316 g) to the solution, the mixture was stirred for 5 hours at normal pressure in hydrogen atmosphere. The reaction solution was filtered through a Celite pad and concentrated to give the title compound, which was used without isolation in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:31][C:32]1[CH:36]=[CH:35][S:34][CH:33]=1>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:31][C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)[CH:9]2[CH2:10][CH2:11][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=3[CH3:28])=[O:20])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: BrCc1ccsc1
Solvent: CC#N
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(Cl)cc2)CC1
Yield: 22.9 %

Procedure:
A solution of the above aniline (119 mg, 0.29 mmol) and 3-(bromomethyl)thiophene (61 mg, 0.34 mmol) in CH3CN (5 mL) was stirred at room temperature overnight to afford COMPOUND 292 as a white solid (34 mg, 23%) following work-up and purification. 1H NMR (CDCl3) δ 0.89-1.19 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.54-1.58 (m, 1H), 1.73-1.80 (m, 3H), 2.16 (t, 1H, J=12.3 Hz), 2.52 (s, 6H), 2.56 (t, 1H, J=12.3 Hz), 2.73-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.49-3.57 (m, 1H), 3.82 (s, 2H), 3.84-3.92 (m, 1H), 6.54 (d, 2H, J=8.7 Hz), 6.98-7.01 (m, 2H), 7.06-7.09 (m, 2H), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 8.71 (br s, 1H), 8.88 (s, 1H). ES-MS m/z 512 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15](=[S:17])[NH2:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.Br[CH2:22][C:23](=O)[CH2:24][CH3:25]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[S:17][CH:22]=[C:23]([CH2:24][CH3:25])[N:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCC(=O)CBr
Reactant: NC(=S)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Solvent: C1COCCO1
Product: CCc1csc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)n1
Reaction time: 2 h

Procedure:
57.5 mg (0.19 mmol) of 4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine (see Example 10) and 34 ml of 1-bromo-2-butanone (Aldrich; Milwaukee/USA) in 3 ml of dioxane are heated to boiling for 2 h. Cooling, filtering the suspension and washing with isopropanol/diethyl ether yields 4-(3-chloroanilino)-6-(4-ethylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=13.6; FAB-MS: (M+H)+=356.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:26][O:27][C:28]2[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CC1
Yield: 47.4 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (370 mg, 1.132 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (327 mg, 1.583 mmol) and sodium ethoxide (154 mg, 2.264 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to afford 276 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 0.30-0.34 (m, 2H), 0.54-0.60 (m, 2H), 1.17-1.24 (m, 1H), 3.79 (d, J=7.2 Hz, 2H), 3.84 (s, 3H), 6.84-6.87 (m, 1H) 6.96-7.00 (m, 4H) 7.31 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.96 (d, J=4.8 Hz), 8.33 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 515.18 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([C@H:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].Cl>C(Cl)Cl.CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([C@H:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: C[C@H](c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.1 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.197 g, 0.383 mmol) in DCM (1 mL) was added 4 N HCl (1.92 mL, 7.66 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure and ether (5 mL) was added. The suspension was stirred at ambient temperature for 10 minutes and the solid formed was collected by filtration to give (S)-1-((R)-1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl) pyrrolidin-3-amine (0.186 g, 92.8%) as solid. LCMS APCI (+) m/z 415 (M+H).