Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C([N:34](CC)CC)C.N>CN1C(=O)CCC1.CCOC(C)=O>[NH2:34][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(F)ccc1-c1nc(N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 43 %

Procedure:
To a solution of the product of Example 48 (1.0 g, 2.2 mmol) and triethylamine (1 mL) in 2 mL of NMP was bubbled NH3 gas at 23° for 30 min. The mixture was diluted with EtOAc and washed with H2O to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, gave the title compound, (360 mg, 43%). LC-MS: 383.0 (MH+, m/z), 1.95 (Rt, min).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:3])[NH2:2].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([O:13][C@@H:22]1[CH:23]2[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]2)[CH2:21]1)=[O:12])(=[O:3])[NH2:2]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: NC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A mixture of 2-(2-carbamoylthiophen-3-ylamino)-2-phenylacetic acid (I7) (389 mg, 1.41 mmol), (R)-quinuclidin-3-ol (215 mg, 1.69 mmol), DCC (349 mg, 1.69 mmol) and HOBT (259 mg, 1.69 mmol) in dry THF (5 ml) was stirred at room temperature overnight. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by preparative HPLC. The fractions with the product are combined and evaporated to dryness. The residue was dissolved in 2M K2CO3 and extracted twice with EtOAc to obtain (R)-quinuclidin-3-yl 2-(2-carbamoylthiophen-3-ylamino)-2-phenylacetate (32 mg, 6% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C.O.[NH2:22][NH2:23]>C(O)CC>[CH3:1][N:2]([CH2:7][C:8](=[N:22][NH2:23])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: NN
Reactant: COC(=O)N(C)CC(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCCO
Product: COC(=O)N(C)CC(=NN)c1ccc(Cl)cc1
Yield: 70.7 %

Procedure:
101 g (418 mmol) of 2-(N-methyl-N-(methoxycarbonyl)-amino)-4′-chloroacetophenone was dissolved in 600 ml of warm 1-propanol. To this mixture was added 4.85 g (80 mmol) of acetic acid and 60.9 g (1218 mmol) of hydrazine monohydrate. The mixture was refluxed for two hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over magnesium sulfate, filtering, and reconcentrating in vacuo, there was obtained 75.6 g of the title compound, an oil.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>CO.[Pd]>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[CH2:23][NH:22][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)/C=C/c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CCC(=O)O)cc3)CC2)ccc1O
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A solution of (E)-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-acrylic acid (which was obtained in Example 170) (0.10 g, 0.40 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methane-sulfonamide (which was obtained in Example 10) (0.12 g, 0.48 mmol) in methanol (15 mL) was treated with avetic acid (0.03 g, 0.5 mmol), and 0.05 g of 10% Pd/C. The mixture was hydrogenated at 25 psi for 24 h, and then filtered through Celite and evaporated. The residue was triturated with ether to give 0.18 g of an off-white solid; m.p. 130–133° C.; 1H NMR (DMSO-d6) δ 1.30–1.46 (m, 2 H), 1.84–1.95 (m, 2 H), 2.37–2.50 (m, 4 H), 2.60–2.78 (m, 4 H), 2.92 (s, 3 H), 3.53–3.62 (m, 3 H), 4.46–4.55 (m, 1 H), 6.85 (d, 2 H), 6.92–7.10 (m, 4 H), 7.18 (dd, 1 H); MS (ES) m/z: 478.3 (MH+).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[C:12]1([N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:20]1([N:18]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:2]3[CH2:3][C:4]4[C:9]([C:1]2=3)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCc2ccccc21
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: c1ccc(-n2c3c(c4ccccc42)Cc2ccccc2-3)cc1

Procedure:
The general procedure of Example A is followed. The reaction of 1-indanone and N,N-diphenylhydrazine hydrochloride gives 5-phenyl 5,10-dihydroindeno[1,2-b]indole. It then reacts with n-butyllithium to produce its lithium salt, which in turn reacts with zirconium tetrachloride to produce Catalyst II.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]=[O:4].[CH2:9]([Mg]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH:3]([OH:4])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C=CCC(C)(C)C=O
Solvent: CCOCC
Product: C=CCC(C)(C)C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethylpent-4-enal (11.2 g) in 200 mL of Et2O cooled to 0° C. was added dropwise a solution of benzylmagnesium chloride (70 mL, 2M in THF). After stirring for 1 h at 0° C., the reaction was quenched with 200 mL of saturated solution of NH4Cl and the product was extracted with 200 mL of 1:1 EtOAc/hexane. The extract was dried over Na2SO4 and concentrated. The residue was distilled under reduced pressure to give 16 g of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C(OC(=O)[N:27]([C:37]1[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[C:39]([CH3:45])[N:38]=1)[CH2:28][C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)(C)(C)C>>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([CH2:28][NH:27][C:37]2[N:38]=[C:39]([CH3:45])[C:40]([C:43]([C:2]3[C:10]4[CH:9]=[N:8][CH:7]=[N:6][C:5]=4[NH:4][CH:3]=3)=[O:44])=[CH:41][CH:42]=2)=[CH:34][CH:33]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(C)n2)cn1
Product: COc1ccc(CNc2ccc(C(=O)c3c[nH]c4ncncc34)c(C)n2)cn1

Procedure:
{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-2-methyl-pyridin-3-yl}-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone P-0019 was prepared in two steps from 5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 38 and (5-formyl-6-methyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 74 as shown in Scheme 14.
Reaction SMILES: O[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:31])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:31][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(Oc2ccc(CO)cc2)nc1)c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc(CCl)cc2)nc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[6-(4-hydroxymethylphenoxy)pyridin-3-yl]-4-trifluoromethylbenzamide (3.06 g, 7.9 mmol) in dichloromethane (90 mL) was added thionyl chloride (1.7 mL, 23.3 mmol), and the resulting solution was stirred for 4 hours at room temperature. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was washed with diethyl ether, to thereby yield 2.95 g of the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C@@H:15]([O:49][C:50](=[O:61])[CH2:51][CH2:52][NH:53]C(OC(C)(C)C)=O)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([C:30]#[N:31])=[C:28]([S:32][CH2:33][C:34]3[N:35]=[C:36]([C:39]4[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=4)[O:37][CH:38]=3)[N:27]=[C:26]([NH2:46])[C:25]=2[C:47]#[N:48])=[CH:20][CH:19]=1)=[O:12])=O)(C)(C)C.[ClH:62]>ClCCl.C(OCC)C>[ClH:45].[ClH:62].[NH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C@@H:15]([O:49][C:50](=[O:61])[CH2:51][CH2:52][NH2:53])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([C:30]#[N:31])=[C:28]([S:32][CH2:33][C:34]3[N:35]=[C:36]([C:39]4[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=4)[O:37][CH:38]=3)[N:27]=[C:26]([NH2:46])[C:25]=2[C:47]#[N:48])=[CH:20][CH:19]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](COC(=O)CCN)OC(=O)CCN)cc1
Reaction time: 1 h

Procedure:
An amount of 123 mg (0.140 mmol) of the compound from example 28A was introduced in 2 ml of dichloromethane and admixed with 1.4 ml (2.807 mmol) of a 2M solution of hydrogen chloride gas in diethyl ether. After 1 hour of stirring, the precipitated solid was isolated by filtration, washed with dichloromethane and diethyl ether and dried under reduced pressure. This gave 79 mg (75% of theory) of the target compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]([C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[N:33](CC3C=CC(OC)=CC=3)[N:32]=[C:31]4[CH3:46])[N:17]=[N:18][C:19]=2[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>>[CH3:46][C:31]1[C:30]2[C:34](=[CH:35][CH:36]=[C:28]([C:16]3[N:17]=[N:18][C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:15]=3)[CH:29]=2)[NH:33][N:32]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4nnc(CCc5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3nnc(CCc4ccccc4)c(N4CCNCC4)n3)cc12
Temperature: 120 °C
Yield: 72.4 %

Procedure:
To 5-(4-Boc-piperazin-1-yl)-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-6-phenethyl-[1,2,4]triazine 129 (18 mg, 0.029 mmol.) was added trifluoroacetic acid (2.5 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 40 minutes. Excess trifluoroacetic acid was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-(3-methylindazol-5-yl)-6-phenethyl-5-(piperazin-1-yl)-[1,2,4]triazine 92 (8.5 mg, 0.021 mmol.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:15]([Cl:16])=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[NH2:18][C@H:19]([C@@H:23]([OH:25])[CH3:24])[C:20]([OH:22])=[O:21].O>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:15]1[C:8]([Cl:7])=[C:9]([C:10]#[N:11])[CH:12]=[CH:13][C:14]=1[NH:18][C@H:19]([C@@H:23]([OH:25])[CH3:24])[C:20]([OH:22])=[O:21]
Reactant: N#Cc1ccc(F)c(Cl)c1Cl
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)O
Temperature: 75 °C
Reaction time: 16.5 h
Yield: 32.4 %

Procedure:
A 500 mL round bottomed flask was charged with diisopropylamine (11.81 mL, 83.60 mmol) and dry THF (100 mL) then the flask was cooled to −5° C. A 2.5M hexane solution of n-butyllithium (30.87 mL, 77.17 mmol) was then added and the mixture was stirred for 1 h at 0° C. This pre-formed LDA solution was then added via cannula to a −78° C. solution of 2-chloro-4-fluorobenzonitrile (10 g, 64.31 mmol) in THF (100 mL) and the mixture was stirred for 2 h. To this was added a solution of hexachloroethane (16 g, 67.58 mmol) in dry THF (50 mL), and the mixture was allowed to warm to room temperature and stirred for 17 h before being concentrated to furnish a yellow solid (12.15 g) which was used directly in the next step without further purification. K2CO3 (17.8 g, 128.62 mol) was added to a solution of 2,3-dichloro-4-fluorobenzonitrile (12.15 g, 64.31 mol) and (2R,3S)-2-amino-3-hydroxybutanoic acid (11.43 g, 0.096 mol) in DMSO (150 mL) at room temperature. The reaction mixture was heated to 75° C. and stirred for 16.5 h, then was allowed to cool to room temperature whereupon water (150 mL) and ethyl acetate (150 mL) was added to the mixture which was then partitioned. The aqueous phase was then washed with EtOAc (70 mL) and the acidified with citric acid monohydrate (19 g). The aqueous phase was then extracted with EtOAc (180 mL) (×2) and the combined organics were washed with water (80 mL), dried (Na2SO4), filtered and concentrated to furnish the title compound as a brown solid (9 g, 48%). 1H NMR (500 MHz, acetone d6, δ in ppm) 7.61 (d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 6.02 (d, J=7 Hz, 1H), 4.60-4.57 (m, 1H), 4.39-4.37 (m, 1H) and 1.38 (d, J=7 Hz, 3H).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:19]2[C:14](=[CH:15][CH:16]=[N:17][C:18]=2[O:31][CH:32]([CH3:34])[CH3:33])[NH:13][C:12]=1[CH3:35])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[CH:32]([O:31][C:18]1[N:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:29])([F:30])[F:28])[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:35])[NH:13]2)([CH3:34])[CH3:33]
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Agent: [Pd]
Solvent: CCO
Product: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1

Procedure:
17 g (0.0352 mole) (-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid benzyl ester is taken up in 340 mL ethanol and hydrogenated without the use of pressure at 20° C. in the presence of 6.8 g 10% palladium/charcoal (50% moist). The catalyst is filtered off and the filtrate evaporated to dryness at 35° C. on a rotary evaporator. Yield: 15.1 g (89.2% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][CH:21]=1)#[N:19]>C(#N)C>[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25][S:11][C:8]2[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][N:9]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(SCC(=O)c2ccc(C#N)cc2)[nH]1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution 4-ethoxycarbonylimidazole-2-thiol (8.22 g, 47.8 mmol) and potassium carbonate (19.8 g, 143 mmol) in dry acetonitrile (100 mL) at room temperature was added 4-cyanophenacyl bromide (10.7 g, 47.8 mmol). The reaction mixture was stirred for 20 hours, during which time a white precipitate formed. To the solution was added 100 mL ice water. The resulting solid was filtered and washed with water (2×25 mL) to provide the title product as an off-white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[C@H:18]3[C@H:13]([N:14]([C:19]([NH:21][CH2:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[OH-].[Li+]>CO>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[C@H:18]3[C@H:13]([N:14]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[O:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)=[N:3][CH:2]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2CCC[C@@H]3[C@H]2CCN3c2ncnc3[nH]ccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CNC(=O)N2CCC[C@@H]3[C@H]2CCN3c2ncnc3[nH]ccc23)cc1
Reaction time: 18 h

Procedure:
To methyl 4-[({[(3aR,7aR)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-4H-pyrrolo[3,2-b]pyridine-4-yl]carbonyl}amino)methyl]benzoate (TFA salt) from Example 23 (8.2 mg, 0.015 mmol) was added MeOH (75 μL) and aqueous lithium hydroxide (299 μL, 0.149 mmol, 2.0 M) solution at 22° C. The reaction was stirred for 18 hours before being concentrated and dissolved in DMSO (2.0 mL). The resulting solution was purified by mass triggered reverse phase HPLC. Lyophilization of the desired fractions gave the title compound (TFA salt). LRMS calc'd for C22H25N6O3 [M+H]+, 421; found 421. Jak1 activity: +.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:6]([CH:9]=1)[CH:7]=[O:8].C1(C)C=CC(S([CH2:30][N+:31]#[C-:32])(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]([C:7]2[O:8][CH:32]=[N:31][CH:30]=2)[CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(Br)cc(C=O)c1OCOCC[Si](C)(C)C
Solvent: CO
Product: COc1cc(Br)cc(-c2cnco2)c1OCOCC[Si](C)(C)C

Procedure:
1 g of 5-bromo-3-methoxy-2-(2-trimethylsilanylethoxymethoxy)benzaldehyde and 0.54 g of p-toluenesulfonylmethyl isocyanide are dissolved in 40 ml of methanol, 0.38 g of o-potassiumcarbonate is added in portions, and the reaction mixture is heated to reflux for 18 h. The solvent is then distilled off, and the crude product is purified by silica gel chromatography (ethyl acetate/heptane).
Reaction SMILES: [CH:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[CH:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:26]\[NH:27][C:28]([NH2:30])=[O:29])/[C:8]1=[O:9])([CH3:2])[CH3:3]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)Cc1ccccc1
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)Cc1ccccc1
Yield: 52.7 %

Procedure:
By using 1-[2-(N-isopropylbenzylamino)ethyl]isatin and semicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out to obtain (E)-1-[2-(N-isopropylbenzylamino)ethyl]isatin 3-semicarbazone having a melting point of 193°-194° C. (yield: 52.7%, recrystallizing solvent: ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH3:14])=[CH2:13].[Br:20]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([CH2:14][Br:20])=[CH2:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccccc1OCc1ccc(Cl)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)c1ccccc1OCc1ccc(Cl)cc1Cl
Reaction time: 12 h
Yield: 41 %

Procedure:
2-[2-(2,4-Dichlorobenzyloxy)phenyl]-1-propene (1.0 g, 3.41 mmole), N-bromosuccinimide (0.61 g, 3.41 mmole) and azobisisobutyronitrile (2.8 mg, 0.017 mmole) were suspended in carbon tetrachloride (4 ml) and the suspension was refluxed with stirring for 12 hours. Then, the mixture was poured into water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water (50 ml) and dried over anhydrous soidum sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to chromatography on a silica gel column and eluted with n-hexane to obtain the title compound (0.52 g, 41.0%). 1H-NMR (CDCl3, δ): 4.50 (s, 2H, CH2Br), 5.20 (s, 2H, ##STR49## 5.33 (d, 1H, =CH), 5.57 (d, 1H, =CH), 6.80-7.57 (m, 7H, aromatic).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)CC)C.O>CCOCC>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([NH:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([C:9]([F:8])([F:17])[F:18])[CH:11]=1)=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.3 %

Procedure:
A solution of pivaloyl chloride (3.62 g; 30 mmol) in 40 ml dry ether was added dropwise at room temperature to a mixture of 3-trifluoromethyl-aniline (4.83 g, 30 mmol) and triethylamine (4.25 ml, 30.5 mmol). This was stirred at room temperature for a period of 14 hours and then poured into 200 ml water, extracted with ether (2×100 ml). The combined ether extracts were washed successively with 0.5 HCl (100 ml); water (2×50 ml); 7% KOH (100 ml) and water (2×50 ml). The ether solution was dried with MgSO4 and concentrated in vacuo to give a white solid (7.23 gm, 98%, m.p. 112.5° C.). The 2,2-dimethyl-3'-trifluoromethyl-propionanilide was recrystallized with dichloromethane and petroleum ether mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH:15]2[CH3:29])[CH:3]=1.[CH:30]1C=CC(CS(Cl)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C:24]3[CH:30]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:21])=[O:22])[CH2:16][CH:15]2[CH3:29])[CH:3]=1
Reactant: CC1CN(S(=O)(=O)c2ccccc2)CCN1Cc1cc(Cl)ccc1OCC(=O)O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CC1CN(S(=O)(=O)Cc2ccccc2)CCN1Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Prepared by the method of example 30, using the product of example 53 part (b) and benzenemethanesulfonyl chloride to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C=C(C=C(C(F)(F)F)C=1)C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(O)c1cc(Cl)cc(C(F)(F)F)c1
Agent: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Product: CC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Yield: 86 %

Procedure:
The title compound was prepared from 1-(3-chloro-5-(trifluoromethyl)phenyl)ethanol (Reference Example 32) by a procedure similar to the one described for 3-chloro-5-(trifluoromethyl)benzaldehyde (Reference Example 31) to provide 1-(3-chloro-5-(trifluoromethyl)phenyl)ethanone (0.998 g, 86%) as a pale yellow oil.