Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:21](Cl)=[N:20][CH:19]=[N:18][C:17]=4[N:16]([C@H:24]4[CH2:29][CH2:28][C@H:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[CH:15]=3)=[CH:10][C:9]=2[CH3:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.COC1C=C(C2C3C(N)=NC=NC=3[N:59]([C@H]3CC[C@H](N4CCN(C)CC4)CC3)C=2)C=CC=1OC1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[CH3:37][C:9]1[CH:10]=[C:11]([C:14]2[C:22]3[C:21]([NH2:59])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[CH2:26][CH2:25]3)[CH:15]=2)[CH:12]=[CH:13][C:8]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1Oc1ccccc1
Reactant: Cc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(Cl)c23)ccc1Oc1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1Oc1ccccc1

Procedure:
The title compound was prepared in a 75% yield from trans-4-{4-chloro-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl phenyl ether in a similar manner to that described for the preparation of trans-5-(3-methoxy-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine acetate: 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.42(m, 4H), 7.37(t, 2H), 7.27(m, 1H), 7.10 (t, 1H), 6.97(m, 3H), 6.11(bs, 2H), 4.55(m, 1H), 2.2-2.6(m, 9H), 2.22(s, 3H), 2.14 (s, 3H), 1.7-2.0(m, 6H), 1.45(m, 2H); MS MH+497.4; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 5%-100% acetonitrile—0.05 M ammonium acetate over 25 min, 1 ml/min) tr 15.93 min.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][NH:3]1.C([Li])(CC)C.C1CCCCC1.[CH3:28][S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH3:28][S:29]([NH:32][C:33]([N:3]1[CH2:4][C@H:5]([NH:6][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:16])[C:2]1=[O:1])=[O:34])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)N=C=O
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: -75 °C
Reaction time: 0.03 h
Yield: 53.8 %

Procedure:
A stirred suspension of (S)-(2-oxo-3-azetidinyl)carbamic acid, phenylmethyl ester (2.20 g; see example 1C) in 60 ml of dry tetrahydrofuran under nitrogen was warmed using a water bath at 40° C. until solution occurs. The solution was cooled to -75° C., and 7.4 ml of 1.35 M sec-butyl lithium in cyclohexane (10 mmol) was added. After stirring for 2 minutes, (methylsulfonyl) isocyanate (about 1.20 g) was added. This reaction was stirred at -75° C. for 10 minutes and poured into 100 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer. Ethyl acetate was added, and the pH was adjusted to 7. After several extractions with ethyl acetate, the aqueous layer was covered with ethyl acetate and adjusted to pH 2. Repeated extraction with ethyl acetate gave an acidic extract, which was dried (sodium sulfate) and evaporated to a residue (2.61 g). Chromatography of this residue on 250 g of silicAR CC-4 using dichloromethane and then 1% methanol in dichloromethane provided 1.82 g of product as a residue.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11]CC)=[O:10])=[O:7].[OH-].[K+]>O1CCOCC1.O>[Cl:23][C:21]1[CH:22]=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([OH:11])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][C:20]=1[F:24]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Yield: 106.7 %

Procedure:
3.44 g of 80 percent strength sodium hydride are added in portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylaminoacrylate in 300 ml of anhydrous dioxane, while cooling with ice and stirring. The mixture is then stirred at room temperature for 30 minutes and under reflux for 2 hours and the dioxane is stripped off in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of potassium hydroxide are added and the mixture is refluxed for 1.5 hours. The warm solution is filtered and the residue is rinsed with water. The filtrate is then acidified to pH 1-2 with half-concentrated hydrochloric acid, while cooling with ice, and the precipitate is filtered off with suction, washed with water and dried in vacuo at 100° C. 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 234°-237° C. are obtained in this manner.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([CH3:10])[CH:3]=1.C1C[O:14]CC1.[OH-].[Na+].OO.Cl>B1C2CCCC1CCC2>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:14])=[C:4]([CH3:10])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1C
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Agent: Cl
Agent: OO
Product: Cc1cc(Br)ccc1CCO
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A solution of 30A (1.5 g, 7.6 mmol) in 0.5 M 9-BBN in THF (40 mL, 20 mmol) was heated at 120° C. in a sealed tube for 15 min in a microwave. The mixture was cooled to 0° C. in a 250 mL Erlenmeyer flask. NaOH (1.0 M, 40 mL) then H2O2 (30%, 40 mL) were added slowly dropwise while maintaining the internal temperature below 30° C. HCl (1.0 M, 40 mL) was added and the mixture was extracted with Et2O (2×100 mL). The organics were combined, washed with NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo. The crude oil was purified by flash chromatography (0% to 50% hexanes in EtOAc) to yield 30B (1.05 g, 64%) as a clear oil. 1H NMR (400 MHz, MeOD) δ ppm 2.30 (s, 3 H) 2.80 (t, J=7.20 Hz, 2 H) 3.69 (t, J=7.07 Hz, 2 H) 7.06 (d, J=8.08 Hz, 1 H) 7.23 (dd, J=8.21, 1.89 Hz, 1 H) 7.28-7.31 (m, 1 H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([CH3:16])=[CH:18][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccc(C)cc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2CCc2ccc(C)cc2)C1
Yield: 10 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (100 mg, 0.5 mmol), 4-methylstyrene (1 mL, 6.72 mmol) and NaH (200 mg, 5 mmol) in DMF (4 ml) at 150° C. for 16 h to obtain 16 mg of 2-ethyl-2,3,4,5-tetrahydro-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCO.N>C(Cl)Cl.[Rh]>[C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCCCC1
Agent: [Rh]
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: NCC1(c2ccccc2)CCCCC1

Procedure:
A mixture containing 1-phenyl-1-cyclohexane-carbonitrile (5.0 g, 27.0 mmol), 150 ml of EtOH, 35 ml of ammonia and 5% rhodium on alumina (1.0 g) was reacted for 12 hours at 80° C. and 500 psi. The mixture was filtered and the filtrate was concentrated in vacuo to provide an oil. This oil was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, filtered and then concentrated in vacuo.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C1COCC1>[C:31]([C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(C#N)ccc12
Temperature: -75 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To tert-butyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (54.6 g, 160.5 mmol) in THF (500 mL) at −75° C. was added chlorosulfonyl isocyanate (17.5 mL, 200.6 mmol) in THF (100 mL) dropwise over a 30 minutes period keeping the temperature below −70° C. and the mixture was stirred at −75° C. for 1 hr. To this mixture was added DMF (37.3 mL, 481.5 mmol) dropwise at −75° C. and the mixture was warmed to ambient temperature, stirring for a total of 2 h. The mixture was quenched with 1 L of 1N NaOH and transferred to a separatory funnel with 500 mL of methyl-tert-butyl ether. The aqueous phase was separated and extracted with an additional 500 mL of methyl-tert-butyl ether. The combined organic phases were washed twice with 500 mL of brine, dried over MgSO4, filtered and concentrated in vacuo to yield a crude mixture that was purified by column chromatography with a 0-100% EtOAc/hexane gradient to yield tert-butyl 1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (45 g, 76%) as an oil that crystallized upon standing. ESI-MS m/z calc. 365.2. found 266.2 (M-Boc+1)+. Retention time: 2.43 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]([N+:17]([O-])=O)=[C:6]([CH:8]([CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[C:9]#[N:10])[N:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[ClH:29].[OH-].[NH4+]>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[NH:17][C:9]([NH2:10])=[C:8]([CH2:11][C:12]3[CH:16]=[CH:15][S:14][CH:13]=3)[C:6]=2[N:7]=1.[ClH:29]
Reactant: N#CC(Cc1ccsc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Product: Nc1nc2c(Cc3ccsc3)c(N)[nH]c2c(=O)[nH]1
Temperature: 90 °C

Procedure:
To a solution of 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(3-thienylmethyl)-4-pyrimidineacetonitrile prepared above (5.0 g) in 1N NaOH (300 mL) is added sodium dithionite (20 g). The reaction mixture is heated for 30 min at 90° C. and then is acidified (pH 1) with mono HCl while still hot. The reaction mixture is cooled and neutralized with ammonium hydroxide. The resulting precipitate is collected by filtration, washed with cold water and dried under vacuum. The crude product is added to 100 mL conc HCl in small portions with stirring and the hydrochloride salt is collected by filtration. The product is recrystallized from 1N HCl to give 2,6-Diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo [3,2-d]pyrimidine-4-one as the monohydro-chloride salt (2.35 g), mp>85° C. (dec). ##STR20##
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[CH:6]\[CH:7]=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)C.[OH-].[Na+]>CO>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:7]/[CH:6]=[CH:5]\[C:4]([OH:25])=[O:3])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C\C=C(c1cccc(OC)c1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C(=C/C=C\C(=O)O)c2cccc(OC)c2)c1
Yield: 99.1 %

Procedure:
In a similar fashion, (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid ethyl ester (2.2 g) in methanol (15 mL) was hydrolyzed using 2N sodium hydroxide solution (5 mL). The usual work up furnished 2.0 g of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid. Crystallization of a portion from ether furnished the analytically pure acid, mp 178°-180° C. Anal. Calculated for C19H18O4C: 73.53; H, 5.85 Found: C, 73.29; H, 5.91.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:26])[C:7]=2[CH:17]=1
Reactant: OCc1ccc2c(c1)Sc1ccccc1CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: O=S1c2ccccc2CCc2ccc(CO)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 2 gm. of 3-hydroxymethyl-10,11-dihydrodibenzo[b,f]thiepin in 200 ml. of methylene chloride at room temperature. Add 1.7 gm. of m-chloroperbenzoic acid. Stir at room temperature for 2 hours. Add 4 gm. of calcium hydroxide and 50 ml. of methylene chloride. Continue stirring for 15 minutes. Filter through celite and evaporate the filtrate to dryness. Crystallize the residue from toluene to obtain the title product (m.p., 144°-146° C.).
Reaction SMILES: C([N:11]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28])(OCC1C=CC=CC=1)=O.[CH2:38]([N:40](CC)[CH2:41][CH3:42])[CH3:39].N1CCCC1>CCOCC>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:40]2[CH2:41][CH2:42][CH2:39][CH2:38]2)=[O:34])=[CH:36][CH:37]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)OCc2ccccc2)cc1
Solvent: C1CCNC1
Solvent: CCOCC
Product: O=C(c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)N1CCCC1

Procedure:
A solution of 6.0 g. of 4-[N-carbobenzyloxy-N-(16-bromohexadecyl)amino]benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 1.1 g. of pyrrolidine. After 1 hour at reflux, the precipitate is filtered off and washed with warm ether. After evaporation in dryness, the intermediate is dissolved in 50 ml. 30% hydrobromic/acetic acid and warmed at 50° for 2 hours. The solvents are evaporated and the product is partitioned between methylene chloride and water. The layers are separated and the methylene chloride is evaporated. The residue is crystallized from acetone to yield colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:16][NH:17][CH2:18][CH:19]=[O:20]>C(OCC)(=O)C>[CH3:16][N:17]([CH2:18][CH:19]=[O:20])[C:14]([NH:13][C:11]1[S:12][C:8]([C:2]2([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: CC1(c2nnc(N=C=O)s2)CCCCC1
Reactant: CNCC=O
Solvent: CCOC(C)=O
Product: CN(CC=O)C(=O)Nc1nnc(C2(C)CCCCC2)s1

Procedure:
A mixture of 5-(1-methylcyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (7.5 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (5 grams) and ethyl acetate (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-{1-methyl-3[5-(1-methylcyclohexyl)-1,3,4-thiadiazol-2-yl]ureido}acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][C@@H:12]([OH:16])[CH2:13][O:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:16][C@@H:12]([CH3:11])[CH2:13][O:14][CH3:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(O)cc(Br)c1
Reactant: COC[C@@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(Br)cc(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
3-Bromo-5-methoxyphenol (7.60 g, 37.4 mmol) synthesized in Example (1a) was dissolved in toluene (100 mL), and R-(−)-1-methoxy-2-propanol (4.40 mL, 44.9 mmol) and triphenylphosphine (13.8 g, 52.6 mmol) were added, followed by dropwise addition of diethyl azodicarboxylate (2.2 mol/l toluene solution, 24 mL, 52.8 mmol) at 0° C. and stirring at room temperature for 1.5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, diethyl ether (100 mL) was added, and the deposit was filtered to be removed. The mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (9.22 g, yield 89%) as a colorless liquid.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][C:4]#[CH:5].CCN(CC)CC.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21].C(Cl)Cl.CCOC(C)=O>ClCCCl>[CH2:1]([N:6]1[CH2:7][CH2:8][N:9]([C:20]([O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:21])[CH2:10][CH2:11]1)[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCN1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C#CCCCN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 64.8 %

Procedure:
A solution of 1-(pent-4-ynyl)piperazine (2.2 g) and Et3N (22 mL) in 1,2-dichloroethane (22 mL) was treated with p-nitrophenyl chloroformate (2.9 g) at rt for 10 min. Work-up and silica gel chromatography (DCM:EtOAc 1:3→0:3) gave 4-nitrophenyl 4-(pent-4-ynyl)piperazine-1-carboxylate as a yellow oil (2.96 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](OCC2C=CC=CC=2)=O)[CH:4]2[CH2:18][CH2:19][N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH:3]12.Br.C(O)(=O)C.C(Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]2[N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:19][CH2:18][CH:4]12)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CC1CCN(C(=O)OCc2ccccc2)C2CCN(c3ncnc4[nH]ccc34)C12
Agent: Br
Solvent: CC(=O)O
Product: CC1CCN(Cc2ccccc2)C2CCN(c3ncnc4[nH]ccc34)C12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product of Example 20 (40 mg, 0.102 mmol), was added HBr in acetic acid (1.5 mL, 0.102 mmol) and the reaction was stirred at room temperature for 2 hours before being concentrated in vacuo and azeotroped with heptanes (×2) and MeOH/heptanes (×1). The residue was taken up in methanol and passed through a Varian StratoSpheres™ SPE PL-HCO3 MP SPE resin. The solution was concentrated in vacuo and taken back up in MeOH (0.10 mL) and an additional amount of benzyl bromide (12.2 mg, 0.0714 mmol) was added and the reaction was stirred at 40° C. for 16 hours. The reaction was concentrated in vacuo and purified by mass triggered reverse phase HPLC. Lyophilization of the desired fractions gave the title product (TFA salt) as a white solid. LRMS calc'd for C21H26N5 [M+H]+, 348; found 348. Jak1 activity: ++.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:19]2[CH:20]=[CH:21][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CC(C)(C)c1ccccc1
Product: CC(C)(C)c1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and tert-butylbenzene.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[ClH:17].[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH2:20][CH2:19]1>>[ClH:17].[CH:18]1([C:21]2[C:22]([N:31]3[CH2:36][CH2:35][N:34]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:16][CH:15]=4)=[O:14])[CH2:33][CH2:32]3)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3C3CC3)CC2)cc1
Yield: 111.9 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (221 mg) described in Preparation Example 37 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride (615 mg) described in Preparation Example 76, the title compound (571 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:59][C:60]1[CH:72]=[CH:71][CH:70]=[CH:69][C:61]=1[O:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C=O)C.O>[Cl:59][C:60]1[CH:72]=[CH:71][CH:70]=[CH:69][C:61]=1[O:62][CH:63]1[CH2:68][CH2:67][N:66]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:19][N:18]=2)=[O:21])[CH2:65][CH2:64]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reactant: Clc1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol), HOBt (0.065 g, 0.000482 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 230-400 mesh (70% ethyl acetate in hexane) afforded 0.153 g (73%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 546.17 (M+1)+, 97.6%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:17])=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-])=O>[C].[Pd].CO>[O:10]([C:7]1[N:6]=[C:5]([NH2:17])[C:4]([NH2:1])=[CH:9][CH:8]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1nc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.9 %

Procedure:
Under a hydrogen stream, a suspension of 3-nitro-6-phenoxy-2-pyridine amine (Compound of Reference Example 114) (0.1 g), palladium-carbon (10 mg) and methanol (2 ml) were stirred at room temperature for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and the fraction eluted with ethyl acetate-hexane (1:1, v/v) was concentrated under reduced pressure to obtain 6-phenoxy-2,3-pyridine diamine (0.06 g, 59%).