Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][C:7]([CH3:30])([CH3:29])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[OH:3][CH2:2][C:1]([NH:6][C:7]([CH3:30])([CH3:29])[CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)=[O:5]
Reactant: O=C(O)CO
Reactant: Cc1cc(Nc2ncnc3cccc(OCC(C)(C)N)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OCC(C)(C)NC(=O)CO)c23)ccc1O
Yield: 53 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-{[5-(2-amino-2-methylpropoxy)quinazolin-4-yl]amino}-2-methylphenol to give 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)-1,1-dimethylethyl]acetamide as a light brown solid in 53% yield; NMR spectrum (DMSO-d6) 1.47 (s, 6H), 3.69 (d, 2H), 4.47 (s, 2H), 7.04 (d, 1H), 7.38 (m, 3H), 7.78 (d, 1H), 7.96 (t, 1H), 8.18 (t, 1H), 8.80 (s, 1H), 10.40 (s, 1H), 10.67 (s, 1H); Mass spectrum MH+ 417.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([NH:13][C:14]1([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1=[O:29])=[O:12].C(O)C>[C].[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([NH:13][C:14]1([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]1=[O:29])=[O:12]
Reactant: CCOC(=O)CCC1(NC(=O)/C=C/c2ccccc2OC)C(=O)N(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCC1(NC(=O)CCc2ccccc2OC)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 719 mg of ethyl 3-[2,3-dihydro-3-[(E)-3-(2-methoxyphenyl)-2-propenoylamino]-2-oxo-1-phenyl-1H-indol-3-yl]propionate, 20 ml of ethanol and 6 ml of tetrahydrofuran was hydrogenated on 100 mg of 10% palladium-carbon under hydrogen gas atmospheric pressure while stirring overnight. The catalyst was filtered off, and the solvent was removed from the filtrate by evaporation to afford 700 mg of ethyl 3-[2,3-dihydro-3-[3-(2-methoxyphenyl)propanoylamino]-2-oxo-1-phenyl-1H-indol-3-yl]propionate as an amorphous solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[N:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[CH:6][C:5]=2[C:4](=[O:22])[CH2:3]1.[Br-].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([OH:22])[C:5]2[CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CC1CC(=O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2C1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(O)c2cc(-c3cccc(C(F)(F)F)c3)nnc2c1
Yield: 5.6 %

Procedure:
To an ethyl acetate solution (1 mL) of 7-methyl-3-(3-trifluoromethylphenyl)-7,8-dihydro-6H-cinnolin-5-one (306 mg, 1.0 mmol) obtained in Example 66 was added cupuric bromide (446 mg, 2.0 mmol), followed by reaction under heating and refluxing for 8 hours, adding saturated sodium bicarbonate aqueous solution (2 mL) to the reaction liquid and extraction with ethyl acetate. To residue obtained after concentration of an organic layer under reduced pressure was added ethyl acetate (1 mL) and filtered off solid obtained to get an objective product (17 mg, 5.5%) as yellow solid.
Reaction SMILES: O1C2(CCC(C3C4C(=CC=CC=4)NC=3)CC2)OCC1.[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:30]3[C:38]4[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=4)[NH:32][CH:31]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[O:23]1[C:24]2([CH2:25][CH2:26][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=4)[NH:32][CH:31]=3)[CH2:28][CH2:29]2)[O:20][CH2:21][CH2:22]1
Reactant: Fc1ccc2c(C3=CCC4(CC3)OCCO4)c[nH]c2c1
Agent: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Product: Fc1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Yield: 60.7 %

Procedure:
This compound was prepared in the manner described above for intermediate 2a by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-6-fluoro-1H-indole (9.54 g) to afford 5.83 g (60%) of the title compound as a white solid: mp 158-159° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[N:3]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[N:3]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Reactant: N[C@H]1CC[C@H](N)CC1
Product: COc1ccc(C(=O)NCCNc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1OC
Product: Cl
Temperature: 140 °C

Procedure:
230 mg of the product obtained in Stage 1 above and 293 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 99 mg of expected product is recovered.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14](OCC)[O:15]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14]=[O:15]
Reactant: CCOC(C#CCCCCCCCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=CC#CCCCCCCCCCCCl
Temperature: 62.5 °C
Yield: 87 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 13-chloro-1,1-diethoxy-2-tridecyne (302.9 g:1.0 mol), para-toluenesulfonic acid (8.0 g:0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and then stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 13-chloro-2-tridecynal [bp: 116-122° C./0.13 KPa, 198.6 g, 0.87 mol]. [Yield: 86.8%]
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.N.[NH2:21]C1C2N=C(C3C=CC(F)=CC=3)C=CC=2N=CN=1>CO>[CH3:1][C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: Nc1ncnc2ccc(-c3ccc(F)cc3)nc12
Agent: N
Solvent: CO
Product: Cc1nc(N)c2nc(-c3ccc(F)cc3)ccc2n1
Yield: 99 %

Procedure:
This compound was synthesized from 2-methyl-4-chloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine and a ammonia solution in methanol in 99% yield, using the procedure described for the synthesis of 4-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine. The mass spectrum was as follows: MS (m/z): 255 ([M+H]+, 100).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:30]([C:29]3[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=3)=[O:31])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: Cc1cc(C(=O)O)n(C)n1
Product: Cc1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(C)sc2-c2cccc(F)c2)n(C)n1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,5-dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=454.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([OH:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CO[CH:24](OC)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[O:20][CH:24]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])[N:6]([C:7]([NH:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[C@H:5]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:21]
Reactant: COC(=O)C(O)C(NC(=O)NC(C)(C)C)c1ccccc1
Reactant: COc1ccc(C(OC)OC)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)NC(C)(C)C)[C@H]1c1ccccc1

Procedure:
N-(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester (PREPARATION 1, 68 mg, 0.23 mM) is dissolved in dry THF (5 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (70 mg, 0.33 mM) and pyridinium p-toluenesulfonate (6 mg, 0.02 mM) and the mixture warmed to reflux. Approximately 2 mL solvent is boiled away 3 times in a 45 minute period replenishing with 2 mL of fresh THF at which time TLC shows no starting material. The solvent is concentrated under reduced pressure and chromatographed (7 g of silica gel packed in ethyl acetate/1hexane, 1/3; elution with 80 mL ethyl acetate/hexane, 1/3; 45 mL ethyl acetate/hexane, 1/2; 30 mL ethyl acetate/hexane, 2/3 and 30 mL ethyl acetate/hexane, 1/1) to give the title compound: less polar isomer found in fractions 21-31--NMR (CDCl3, TMS) 1.19, 3.82, 3.85, 3.89, 4.68, 4.88, 5.52, 6.46, 6.70 and 7.25-7.50 δ, MS (FAB-High Res.) theory for C24H31N2O6 +H=443.2182, found=443.2172; more polar isomer in fractions 33-42--NMR (CDCl3, TMS) 0.99, 3.53, 3.81, 3.88, 4.05, 4.55, 5.45, 6.48, 6.79 and 7.25-7.50 δ; MS (FAB-High Res.) theory for C24H31N2O6 +H=443.2182, found=443.2180.
Reaction SMILES: [Cl:1][C:2]([Cl:25])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)O)[C:3]([O:5][CH3:6])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:2]([Cl:1])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)(Cl)CCCCCCCCCC(O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(Cl)(Cl)CCCCCCCCC=Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
Methyl 2,2-dichloro-12-(4-chlorophenyl)-12-hydroxydodecanoate (8.89 g, 21.91 mmol) was dissolved in 300 ml of toluene. The solution was added with p-toluenesulfonic acid monohydrate (1.67 g, 8.78 mmol), and stirred at 80° C. for 4 hours. The reaction mixture was washed with 200 mL of water and 10 ml of aqueous saturated sodium hydrogencarbonate. The aqueous layer was further extracted with 100 mL of ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The extracts were purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). The solvent was evaporated under reduced pressure to obtain the desired compound (8.38 g, yield 97.6%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=1)=[C:23]=[O:24]>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:23]([NH:22][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=2)=[O:24])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (62 mg, 0.308 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.13 mL, 0.924 mmol.), and 1-isocyanato-4-octylbenzene (0.071 mL, 0.308 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (94 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H, J=8.4 Hz), 7.12 (d, 2H, J=8.4 Hz), 6.45 (bs, 1H), 4.78 (bs, 1H), 4.09 (q, 2H, J=7.2 Hz), 2.90 (s, 2H), 2.58-2.48 (m, 4H), 2.39-2.19 (m, 4H), 2.25 (s, 3H), 1.75-1.70 (m, 2H), 1.60-1.54 (m, 2H), 1.30-1.23 (m, 13H), 0.80 (t, 3H, 6.4 Hz); MS ESI 432.4 [M+H]+, calcd for [C25H41N3O3+H]+ 432.62.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)Oc1ccccc1C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2c(c1)Oc1ccccc1C2
Yield: 96.3 %

Procedure:
A solid mixture of 3-methoxy-9H-xanthene 9 (5.84 g, 27.5 mmole) and pyridine hydrochloride (42 g, 363 mmole) was heated at 200-210° for 2 hrs. The resulting reaction mixture was cooled to about 70° and treated with water, while a precipitate formed. The orange colored solid was filtered on a Buchner funnel, washed with water, and dried in vacuo, yielding the crude 3-hydroxy-9H-xanthene 10 (5.25 g, 96%). No major oxidation took place when crude 10 was stored in a desiccator under argon in the dark. Thus, the crude xanthene 10 was used for silylation without further purification. No 1H NMR or 1R were taken.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:37])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([C:27](=[O:36])[C:28]3[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:35])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:44]([S:47](Cl)(=[O:49])=[O:48])[CH2:45][CH3:46].CC1CCCO1>CN(C1C=CC=CN=1)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[C:19]3[C:11]([C:9]([C:4]4[C:3]([F:37])=[C:2]([NH:1][S:47]([CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])[CH:7]=[CH:6][C:5]=4[F:8])=[O:10])=[CH:12][N:13]([C:27](=[O:36])[C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:35])[C:14]3=[N:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Solvent: CC1CCCO1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 12.5 °C
Yield: 116.9 %

Procedure:
Compound 7 (800 g; 1.44 mol) and dimethylamino pyridine (7.2 g; 0.059 mol), under nitrogen, were added to a 5 L three-necked-round bottom flask cooled in an ice water bath. Anhydrous pyridine (1.8 L) was charged and the mixture was stirred at 10-15° C. until a homogeneous solution was obtained. Propane-1-sulfonyl chloride (308 g; 2.16 mol) was added drop-wise from an addition funnel while keeping the reaction temperature <20° C. and the reaction mixture was stirred at 20-25° C. for 3 h. The reaction mixture was added to a mixture of 2-methyl-THF (7 L) and water (10 L) in a flask and the organic layer was separated, washed with 1N HCl (2 L) followed by brine (2 L), and dried. The residue was azeotroped with toluene to remove the residual water to provide crude compound 9 (1116.4 g) which was used in the next step without purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][O:4]1.[C:15]([O-:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([O-:20])=[O:19].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[CH2:23]([N:25]([CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][O:4]1)[CH2:26][CH3:27])[CH3:24]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CCNCC
Reactant: COc1ccc2c(c1)CCOC2CCl
Product: CCN(CC)CC1OCCc2cc(OC)ccc21
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 5.0 g of 1-chloromethyl-6-methoxyisochroman and 30 ml of diethylamine was heated in a sealed tube at 150°-160° C for 21 hours and, after cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with 100 ml of water and extracted with chloroform. The extract was rinsed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and elution was carried out with a 1:2 mixture of benzene and methanol. The oily product thus obtained was converted to the fumarate and recrystallized from a mixture of methanol and ether. By the above procedure was obtained 1.9 g of 1-diethylaminomethyl-6-methoxyisochroman fumarate as colorless prisms.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@@:28]4(OC)[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClC(Cl)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(C(C)C)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCC4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: -55 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of (2S,3R,4S,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (1.20 g, 2.19 mmol) in acetonitrile-dichloroethane 1:1 (20 mL) was added triethylsilane (1.39 mL, 8.76 mmol) at room temperature, then the reaction mixture cooled to −50 to −60° C. and boron trifluoride diethyletharate complex (0.55 mL, 4.38 mmol) was added dropwise, and the reaction mixture was stirred at same temperature and allowed to stir at below −30° C. for 2 hours and at −20° C. for 1 hour and then below 0° C. for 1 hour. The reaction was quenched with aq. saturated NaHCO3 solution (20 mL). The volatiles were evaporated under reduced pressure, and the resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with brine (5 mL), dried over sodium sulphate, and concentrated to furnish (2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.0 g). Crude product was used for next step without purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][NH:22][CH2:23][CH2:24][OH:25]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:22]([CH2:23][CH2:24][OH:25])[CH3:21])=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: CNCCO
Product: CN(CCO)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 2-(methylamino)ethanol (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-[(2-hydroxy-ethyl)-methyl-amino]-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (29 mg, 29%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O2 (M+H+) 333.2285, found 333.2282.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][C:16]=3[CH:26]=2)[NH:8]1.[OH-].[Na+].Cl>CO>[CH3:6][N:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:16]=3[CH:26]=2)[NH:8]1
Reactant: COC(=O)C1=Cc2cc(C3=NNN(C)N3)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1NN=C(c2ccc3c(c2)C=C(C(=O)O)CCO3)N1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
In methanol (7 ml) and THF (7 ml) was suspended methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (324 mg, 1.13 mmol), and to the mixture was added 1N sodium hydroxide solution (3.4 ml). The mixture was stirred at 50° C. for 4 hours, and to the mixture was added, under ice-cooling, 1N hydrochloric acid(3.4 ml). The mixture was concentrated under reduced pressure, and to the residue was added water. Insoluble materials were filtered, which were washed with water and dried under reduced pressure to give 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (295 mg, 1.08 mmol, 96%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]([NH:11]S(C(C)(C)C)=O)[CH2:9][CH3:10])[CH:4]=[N:3]1.[ClH:18]>CO>[ClH:18].[ClH:18].[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]([NH2:11])[CH2:9][CH3:10])[CH:4]=[N:3]1
Reactant: CCC(NS(=O)C(C)(C)C)c1cnn(C)c1C
Agent: Cl
Solvent: CO
Product: CCC(N)c1cnn(C)c1C
Reaction time: 15 h
Yield: 99 %

Procedure:
N-(1-(1,5-dimethyl-1H-pyrazol-4-yl)propyl)-2-methylpropane-2-sulfinamide (Step A5B) (650 mg, 1.8 mmol) was dissolved in 10% HCl in MeOH (5 ml) and the resulting mixture was stirred for 15 h. The mixture was concentrated to give a pale yellow solid, which was recrystallized (MeOH-Ether) to give the title product as a white solid (460 mg, >99% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.76 (3H, t, J=6.0 Hz), 1.70-1.84 (1H, m), 1.89-2.03 (1H, m), 2.23 (3H, s), 3.72 (3H, s), 3.96-4.03 (1H, m), 7.54 (1H, s), 8.35 (3H, brs).