Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:7]([O:20][CH3:21])[CH:6]=2.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[C:3]([C:22]#[N:23])[C:2]([N:1]=[CH:26][N:27]([CH3:29])[CH3:28])=[CH:11]2)=[CH:6][C:7]=1[O:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc2cc(C#N)c(N)cc2cc1OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COc1cc2cc(C#N)c(N=CN(C)C)cc2cc1OCc1ccccc1

Procedure:
A mixture of 0.12 g (1.7 mmol) of 3-amino-6-benzyloxy-7-methoxynaphthalene-2-carbonitrile and 0.5 mL of N,N-dimethylformamide dimethyl acetal in 2.0 mL of toluene is heated under reflux for 4 hours. The solvent is evaporated and the residue is dried on high vacuum to yield N′-(7-benzyloxy-3-cyano-6-methoxynaphthalen-2-yl)-N,N-dimethylformamidine as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[CH2:16][CH2:17][CH3:18].[Li+].[OH-]>C1COCC1.O>[CH2:16]([C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:19])=[O:2])[CH2:17][CH3:18]
Reactant: CCCc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a suspension of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (220 mg, 0.81 mmol) in THF (3 mL) was added a solution of 1N-LiOH (6 ml), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with H2O, which was washed three times with EtOAc, acidified with 1N HCl to pH 1-2. The resulting solution was extracted three times with methylene chloride and then dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound (155 mg, 74%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C1(C)C=CC=CC=1.[OH:12][CH:13]([CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32])[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[C:21]([O:29][CH3:30])[CH:20]=1)=[O:15].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:30][O:29][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][NH:16][C:14](=[O:15])[CH:13]([O:12][CH2:3][C:2]#[CH:1])[CH:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]#[CH:28]
Reactant: C#CCOc1ccc(CCNC(=O)C(O)C(C)c2ccccc2)cc1OC
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(CCNC(=O)C(OCC#C)C(C)c2ccccc2)cc1OC
Reaction time: 16 h

Procedure:
A 80% solution of propargyl bromide in toluene (1.2 g, 7.8 mmol) is added slowly at room temperature to a mixture of 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)ethyl]-3-phenyl-butyramide (2.4 g, 6.5 mmol), 30% sodium hydroxide solution (6.0 ml, 33 mmol) and catalytic amounts of tetrabutylammonium bromide (50 mg) in 25 ml of dichloromethane. The reaction is stirred for 16 hours at +40° C. Subsequently the mixture is evaporated and the residue is diluted with water and dichloromethane. The phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated. The remaining oil is purified by chromatography on silica gel (ethyl acetate/hexane 1:1) to yield N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-3-phenyl-2-prop-2-ynyloxy-butyramide (E1.24).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[S:45][CH2:44][C:43](=O)[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[S:45][CH2:44][CH2:43][N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)CSc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1CCSc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.570 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.359 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]thiazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=6.14.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH2:9][CH2:10][NH2:11].[OH-].[Na+].C1(C)C=CC=C(O[C:21](=[NH:25])[NH:22][C:23]#[N:24])C=1.C1C(O)=CC=CC=1C>C(O)(C)C>[C:21]([NH:22][C:23]([NH:11][CH2:10][CH2:9][C:5]1[N:6]=[CH:7][NH:8][C:4]=1[CH3:3])=[NH:24])#[N:25]
Reactant: Cc1cccc(OC(=N)NC#N)c1
Reactant: Cc1[nH]cnc1CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1cccc(O)c1
Product: Cc1[nH]cnc1CCNC(=N)NC#N
Temperature: 25 °C

Procedure:
4.94 g. (0.249 mole) 5-methyl-4-(2-aminoethyl) imidazole dihydrochloride is converted to the free base with NaOH. The free base is combined with 4.36 g. (0.0249 mole) of O-m-tolyl-N-cyanoisourea in 63 ml. isopropanol. This mixture is refluxed for one hour. The mixture is then cooled to room temperature, filtered to remove insoluble material, and the solvent is evaporated to obtain a cloudy oil of the product mixed with m-cresol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.[CH:21](O)=O>C(=O)(O)[O-].[Na+]>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[C:2]([NH:1][CH3:21])[CH:7]=1
Reactant: O=CO
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1cc(OC)ccc1C1CCc2cc(O)ccc2C1

Procedure:
A mixture of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (800 mg) and formic acid (8 ml) was refluxed overnight. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting residue according to an analogous synthetic method to Example 337 described below, the title compound (730 mg) was obtained.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]=2[CH:13]=1.[BH4-].[Na+].[C:16](O)(=[O:18])C>C(COC)OC.C(O)(C)C>[CH:9]([NH:8][C:7]1[CH:13]=[CH:3][C:4]([O:18][CH3:16])=[CH:5][C:6]=1[SH:10])([CH3:11])[CH3:12]
Reactant: COc1ccc2c(c1)NC(C)(C)S2
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(C)O
Product: COc1ccc(NC(C)C)c(S)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-methoxy-2,2-dimethylbenzothiazolidine (14.6 gm; 75 mmoles) in 50 ml dimethoxyethane and 5 ml isopropanol was added sodium borohydride (4.0 gm; 0.1 mole). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then poured over 5 N acetic acid, extracted with methylene chloride, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from hexane to yield the title compound, m.p. 68°-69° C. in nearly quantitative yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]1([CH2:7][CH2:8][N:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:18]([CH3:17])(=[O:20])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(CCNCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(CCc1ccccc1)Cc1cccnc1

Procedure:
A 4.4 g. portion of 3-(2-phenylethyl)aminomethylpyridine was reacted with 2.4 g. of methanesulfonyl chloride in the presence of 4 g. of potassium carbonate in 60 ml. of dichloromethane at ambient temperature for several days. The mixture was then diluted with 100 ml. of dichloromethane and extracted with 50 ml. of water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was taken up in toluene and chromatographed on silica gel, eluting with 9:1 toluene:acetone. The product-containing fractions were combined and evaporated under vacuum, and the residue solidified on standing. The solids were triturated in ether and dried to obtain 1.8 g. of the desired product, m.p. 94°-95°.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:32])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:24]2)[O:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[F:67][C:68]([F:79])([F:78])[O:69][C:70]1[CH:71]=[C:72]([NH2:77])[C:73]([NH2:76])=[CH:74][CH:75]=1>C(Cl)Cl>[NH2:77][C:72]1[CH:71]=[C:70]([O:69][C:68]([F:67])([F:78])[F:79])[CH:75]=[CH:74][C:73]=1[NH:76][C:29](=[O:31])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:32])[CH2:24]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)O)C1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)Nc2ccc(OC(F)(F)F)cc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a solution of 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (1.2 g, 2.91 mmol), HATU (2.17 g, 5.83 mmol) and HOAT (0.91 g, 5.83 mmol) in DCM (17 mL) were added 4-(trifluoromethoxy)benzene-1,2-diamine (1.1 g, 5.83 mmol) and TEA (2.05 mL, 14.56 mmol). The mixture was stirred at rt overnight. The mixture was diluted with DCM (50 mL) and washed with water (15 mL×3) and brine (30 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Combi-Flash (40 g silica gel, start EA:DCM MeOH=10:10:0 to 10:10:8 by gradient, 40 mL/min, 50 min, 2.0 L total solvent volume) to afford the desired compound (1.0 g, yield: 60%) as a yellow solid. 1H NMR (500 MHz, MeOD): δH 8.29 (s, 1H), 8.25-8.24 (m, 1H), 7.20-7.13 (m, 1H), 6.95-6.85 (m, 0.4H), 6.73 (brs, 0.8H), 6.54 (d, J=7.5 Hz, 0.8H), 6.22 (d, J=2.0 Hz, 1H), 5.60-5.55 (m, 1H), 5.03-5.00 (m, 1H), 4.40-4.35 (m, 1H), 3.40-3.35 (m, 0.3H), 3.00-2.92 (m, 0.7H), 2.70-2.47 (m, 3H), 2.36-2.28 (m, 2H), 2.20-1.80 (m, 6H), 1.76-1.66 (m, 2H), 1.60 (s, 3H), 1.40 (s, 3H), 1.26-1.16 (m, 1H) ppm; ESI-MS (m/z): 621.3 [M+1]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29][C:30]([O:32][CH2:33][CH:34]4[C:46]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:40]5[C:35]4=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])[CH2:18][CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]>CO.C(O)(=O)C.[Pd]>[NH2:1][C:2]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3([NH:29][C:30](=[O:31])[O:32][CH2:33][CH:34]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=5[C:41]5[C:46]4=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCN(C(=O)OCc4ccccc4)CC3)nc12
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1cccc2[nH]c(C3(NC(=O)OCC4c5ccccc5-c5ccccc54)CCNCC3)nc12
Yield: 65.8 %

Procedure:
A mixture of Example 49A (0.175 g, 0.3 mmol) and 10% Pd/C (0.015 g) in MeOH (5 ml) and acetic acid (0.2 ml), was stirred overnight under a H2 atmosphere at room temperature. The mixture was filtered through a pad of silica then concentrated under vacuum. The residue was purified by HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide 0.095 g (69%) of the desired product. MS (ESI) m/e 482 (M+H)+. 1H NMR (DMSO-D6) δ ppm 8.55 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.82-7.91 (m, 3H), 7.65-7.78 (s, 3H) 7.42 (d, J=7.67 Hz 2H), 7.29-7.34 (m, 2H), 4.31 (d, J=7.06 Hz, 2H), 3.5-3.28 (m, 7H), 2.42 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH3:23])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:27]([CH:33]=O)=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:33][C:27]1[C:26]([CH3:25])=[CH:31][C:30]([CH3:32])=[CH:29][N:28]=1)[CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN(C)C(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of methyl-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-carbamic acid tert-butyl ester, 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}-butyl}-methyl-carbamic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.20-1.29 (m, 4H), 1.41 (s, 9H), 1.60-1.65 (m, 1H), 1.86 (s, 3H), 1.93-2.00 (m, 3H), 2.25 (s, 3H), 2.38 (s, 3H), 2.45-2.890 (m, 7H), 2.96-3.04 (m, 2H), 3.94-4.05 (m, 3H), 7.01 (dd, 1H, J=7.6, 4.6 Hz), 7.19 (s, 1H), 7.30 (d, 1H, J=7.8 Hz), 8.15 (s, 1H), 8.45 (d, 1H, J=3.8 Hz). Conversion to the HBr salt according to General Procedure D gave COMPOUND 370 as a white solid. 1H NMR (D2O) δ 1.39-1.49 (m, 4H), 1.78-1.85 (m, 1H), 2.03-2.21 (m, 2H), 2.40-2.55 (m, 8H), 2.62 (s, 3H), 2.71-2.80 (m, 1H), 2.86-2.91 (m, 2H), 3.00-3.04 (m, 2H), 4.13 (d, 1H, J=17.7 Hz), 4.38 (d, 1H, J=17.8 Hz), 4.47-4.51 (m, 1H), 7.84-7.89 (m, 1H), 8.21 (s, 1H), 8.35 (d, 1H, J=7.9 Hz), 8.46 (s, 1H), 8.60 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 19.41, 19.92, 22.88, 23.03, 26.19, 27.77, 30.23, 35.44, 51.34, 54.26, 63.52, 128.25, 138.90, 139.74, 140.04, 141.74, 143.13, 150.52, 151.24, 151.60, 153.54; ES-MS m/z 353 (M+H). Anal Calcd. For C22H32N4.4.3(HBr).3.3(H2O).0.5(C4H10O): C, 36.17; H, 6.06; N, 7.03; Br, 43.11. Found: C, 36.31; H, 5.93; N, 6.95; Br, 42.84.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[F:14][C:15]([F:34])([F:33])[C:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([OH:27])[C:19]([CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[N:17]=1>CCOCC>[F:34][C:15]([F:33])([F:14])[C:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([O:27][C:7](=[O:9])[CH3:8])[C:19]([CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[N:17]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OC(C)=O
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A mixture of 1.26 g (0.016 mol) of pyridine, 1.61 g (0.016 mol) of acetic anhydride and 5.0 g (0.016 mol) of product of Example 35 in 50 ml of ether was stirred for 3 hours and filtered. The filtrate was concentrated in vacuo to give 5.38 g (95%) of product as a solid; mp 49°-51° C.
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]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[Li+].[OH-]>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]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)=[N:3][CH:2]=1
Reactant: COC(=O)c1ccc(COC(=O)N2CCC[C@@H]3[C@H]2CCN3c2ncnc3[nH]ccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COC(=O)N2CCC[C@@H]3[C@H]2CCN3c2ncnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of the product of Step 1 (11 mg, 0.025 mmol) in MeOH (0.13 mL) was added 0.5 M aqueous LiOH (0.51 mL, 0.25 mmol) and the reaction mixture was stirred for 48 hours at ambient temperature. The reaction mixture was concentrated in vacuo and purified by mass triggered reverse phase HPLC. Lyophilization of the desired fractions afforded the title product (TFA salt) as a white solid. LRMS calc'd for C22H24N5O4 [M+H]+, 422; found 422. Jak1 activity: +.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5](=O)[CH3:6].[NH2:10][C:11]1[NH:15][N:14]=[C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])(=[O:19])=[O:18])[N:12]=1>C(O)(=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[N:12]=[C:11]2[N:10]=[CH:3][CH:4]=[C:5]([CH3:6])[N:15]2[N:14]=1)(=[O:18])=[O:19]
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2Cl)n[nH]1
Reactant: COC(CC(C)=O)OC
Solvent: CC(=O)O
Product: Cc1ccnc2nc(NS(=O)(=O)c3ccccc3Cl)nn12
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A sample of 3.0 ml (2.7 g, 20 mmol) of acetylacetaldehyde dimethylacetal was added to a solution of 2.74 g (10.0 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-chlorobenzenesulfonamide in 20 ml of glacial acetic acid at reflux over 12 hours. After the addition was complete the reaction mixture was heated at reflux for 15 hours and cooled to room temperature. The solid which separated was collected by filtration, washed with acetic acid and dried to yield 1.92 g (59 percent) of the desired product as white solid, mp 267.5°-269° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[N:18]=[C:17]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[C@H:28]2[CH2:33][C@@H:32]([NH:34]C(=O)OC(C)(C)C)[C:31](=O)[C@@H:30]([CH3:43])[CH2:29]2)=[O:20])[CH:16]=[CH:15][C:14]=1[F:44]>CCO.N1C=CC=CC=1>[NH2:34][C@@H:32]1[CH2:33][C@H:28]([C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:21][C:19](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([F:44])=[C:13]([C:7]3[C:6]([F:5])=[CH:11][CH:10]=[CH:9][C:8]=3[F:12])[N:18]=2)[CH2:29][C@H:30]([CH3:43])/[C:31]/1=[N:4]\[O:2][CH3:3]
Reactant: CON
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CO/N=C1/[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1C
Reaction time: 16 h
Yield: 16 %

Procedure:
A solution of methoxylamine-HCl (1.0 equiv.) and tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate (1.0 equiv.) in EtOH/pyridine (1/1, 0.01 M) was capped and left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and Na2CO3 (sat.). The organic layer was washed with NaCl(sat), dried over MgSO4, filtered, concentrated. The Boc group was removed with 25% TFA/CH2Cl2. After 45 minutes, the volatiles were removed in vacuo and the residue was pumped on for 5 minutes, dissolved in CH2Cl2 and neutralized with TEA. The volatiles were removed in vacuo and after pumping the residue was dissolved in DMSO and purified by RP-HPLC to yield N-(4-((1R,3R,5S,E)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 16% yield. LC/MS (m/z)=484.2 (MH+), Rt=0.64 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 8.57 (s, 1H), 8.47 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.25 (broad doublet, J=4.0, 2H), 8.20 (t, J=8.0, 1H), 7.67-7.74 (m, 1H), 7.42 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 4.04-4.08 (m, 1H), 3.79 (s, 3H), 3.23-3.29 (m, 1H), 2.39-2.45 (m, 1H), 2.11 (d, J=8.0, 1H), 2.10 (d, J=8.0, 1H), 1.90 (q, J=12, 1H), 1.40 (q, J=12, 1H), 1.01 (d, J=4.0, 3H); and N-(4-((1R,3R,5S,Z)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 27% yield. LC/MS (m/z)=484.2 (MH+), Rt=0.66 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.57 (s, 1H), 8.47 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1H), 8.08 (broad singlet, 2H), 7.67-7.74 (m, 1H), 7.42 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 3.88-3.92 (m, 1H), 3.80 (s, 3H), 3.22-3.28 (m, 1H), 2.51-2.58 (m, 1H), 2.25 (d, J=12.0, 1H), 1.86 (d, J=12.0, 1H), 1.70 (q, J=12, 1H), 1.62 (q, J=12, 1H), 1.34 (d, J=4.0, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][C:13](=[S:37])[NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Product: CC(C)C1CC(=S)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 120 °C
Yield: 95.4 %

Procedure:
The mixture of racemic (2′S,3R)-6-chloro-2′-(3-chlorophenyl)-4′,4′-isopropylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.15 mmol) prepared in example 3b and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (100 mg, 0.25 mmol) (Aldrich) in toluene (20 mL) was heated at 120° C. for 0.5 h. The mixture was cooled to room temperature and then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:1) to give racemic (2′S,3R)-6-chloro-2′-(3-chlorophenyl)-4′-isopropyl-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one as a white solid (Yield 60 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Cl:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:10])[NH:11][CH:12]=[N:1][C:2]=2[CH:7]=1
Reactant: NC(=O)c1ncc(Cl)cc1N
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2cc(Cl)cnc12
Temperature: 25 °C

Procedure:
A suspension of 3-amino-5-chloro-pyridine-2-carboxamide (3.43 g, 20 mmole) in triethyl orthoformate (50 ml) was refluxed for 3 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane. The title compound was obtained as a white solid (3.4 g, yield 94%) which was characterized by its mass spectrum as follows: MS (m/z): 182.1 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:21]([CH2:24][OH:25])[CH2:22][NH2:23].CCN(C(C)C)C(C)C>CCCCO>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH2:22][CH2:21][CH2:24][OH:25])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: NCCCO
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCCNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 200 °C
Yield: 40 %

Procedure:
165 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 86 mg of propanolamine and 147 mg of DIPEA were dissolved in 2 mL of n-BuOH, The mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. n-BuOH was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH-EtOH solvent mixture. 3-(6-(4-Morpholinophenylamino)pyrimidin-4-ylamino)propan-1-ol was obtained in the form of a colorless solid.