Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCc1cccc(F)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cccc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 62.1 %

Procedure:
A mixture of intermediate 59 (2.0 g, 5.42 mmol), 3-fluorobenzylamine (1.86 mL, 16.2 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and is purified twice by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 1.5 g of the product 87. 1H NMR (CDCl3) δ 7.50 (s, 1 H), 7.40-7.30 (m, 1 H), 7.30-7.15 (m, 2 H), 7.10-6.90 (m, 9 H), 7.85-7.75 (m, 2 H), 5.50-5.30 (m, 2 H), 4.80-4.55 (m, 2 H), 1.15 (s, 9 H); MS: m/z 446 (M++1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[CH3:19][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>CN(C=O)C>[CH3:19][N:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1)[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Reaction time: 0.5 h

Procedure:
Benzyl (4-oxocyclohexyl)carbamate (500 mg, 2.0 mmol) in DMF was treated with lithium hexamethyldisilazid (2.0 mmol) at room temperature. This solution was stirred for 30 min and was then treated with iodomethane (0.25 mL, 4.0 mmol) and stirred for 18 h. DMF was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:33]1([CH:43]([NH2:45])[CH3:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>CN1C(=O)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:10]([NH:9][C:7](=[O:8])[C:6]1[CH:22]=[CH:23][C:3]([CH2:2][NH:45][CH:43]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH3:44])=[CH:4][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(N)c1cccc2ccccc12
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNC(C)c2cccc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
The resin-bound 4-chloromethyl-N-dodecyl-benzamide (described in step b, 0.0426 mmol) was swelled in NMP (0.25 mL) for 15 min at rt. DIEA (33 mg, 0.256 mmol), tetrabutyl-ammonium iodide (94.4 mg, 0.256 mmol) and 1-naphthalen-1-yl-ethylamine (44 mg, 0.256 mmol) dissolved in NMP (0.75 mL) were added and the reaction mixture was shaken 14 h at 80° C. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound N-dodecyl-4-({[1-(1-naphthyl)ethyl]amino}-methyl)benzamide which was used directly in the next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]([Cl:26])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:26][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 180 °C
Yield: 57.3 %

Procedure:
A mixture of (5)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 80 mg), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 9, 122 mg) and DIPEA (0.134 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 min) to give the titled compound as solid (90 mg). NMR 10.34 (s, 1H), 8.91 (s, 3H), 8.30 (s, 1H), 5.94 (s, 1H), 4.96-5.34 (m, 1H), 2.25 (s, 3H), 1.56 (d, 3H); m/z 350.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][O:11][C:5]=2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3]1.[C:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22])#[N:17]>>[OH:22][CH:21]([C:10]1[O:11][C:5]2[C:4]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=1)[C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([C:16]#[N:17])[CH:19]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(C)Cc1nn(C)c(=O)c2ccoc12
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3cccc(C#N)c3)oc12

Procedure:
Prepared from 5-methyl-7-(2-methylpropyl)furo[2,3-d]pyridazin-4(5H)-one (example 35 step d) and 3-cyanobenzaldehyde following the method of Example 35 step e.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:13]4[CH:18]=[CH:17]N=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:28]1(B(O)O)C=CC=CC=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:13]4[CH:14]=[CH:15][CH:28]=[CH:17][CH:18]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: OB(O)c1ccccc1
Product: C[C@@H](Oc1nc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 33.3 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead phenylboronic acid (100.0 mg, 0.82 mmol) as a starting material to afford 32.6 mg (33.3%) of (R)-4-((R)-1-((3-cyclopropyl-6-phenyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl) pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.295 (s, 1H), 8.09 (dd, J=1.8, 5.4 Hz, 2H), 7.801 (s, 1H), 7.57 (s, 1H), 7.45 (t, J=7.2 Hz, 2H), 7.375-7.346 (m, 1H), 5.61-5.74 (m, 1H), 3.73-3.68 (m, 1H), 3.42 (t, J=9.3 Hz, 1H), 3.22 (dd J=6.3, 6.3 Hz, 1H), 2.87-2.82 (m, 1H), 2.34 (d, 9 Hz, 2H), 1.43 (d, J=6.6 Hz, 3H), 1.15-1.03 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C21H22N4O2: 362.17; found 363.09.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:3]1.I[CH:26]([CH3:28])[CH3:27].[H-].[Na+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][CH:4]1[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)[CH:9]=[C:10]([O:11][CH:26]([CH3:28])[CH3:27])[C:5]1=2)[CH3:24]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(O)c21
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC(C)C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of ethyl 2-(1,4-dihydroxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxa-borol-3-yl)acetate (100 mg, 0.30 mmol) and 2-iodopropane (154 mg, 0.91 mmol) in DMF (5 mL) was added 60% NaH (4.85 mg, 1.21 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and quenched by slow addition of water (3 mL). The resulting mixture was acidified with 1 N HCl to pH=4 and extracted with EtOAc (2×15 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow oil (96 mg, yield: 86%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:42][O:43][C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH2:46]>>[CH3:42][O:43][C:44]1[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=1[NH:46][C:30](=[O:31])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)CCOc1nc(N2CCOCC2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy] propionic acid and 2-methoxyaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>O1CCOCC1>[Br:23][C:24]1[CH:25]=[N:26][C:27]([NH:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:2]=2[F:1])=[N:28][CH:29]=1
Reactant: NCc1cc(C(F)(F)F)ccc1F
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzylamine (2.0 g) is dissolved in 1,4-dioxane (10 ml) and thereto are added N,N-diisopropylethylamine (2.7 ml) and 5-bromo-2-chloropyrimidine (3.02 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (1.69 g). MS (m/z): 350/352 [M+H]+
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:8][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13]Cl)[CH3:10].O>CN(C=O)C>[CH3:10][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:8]
Reactant: CC(C)CC(O)(CCl)c1ccccc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(O)(Cn1cncn1)c1ccccc1
Temperature: 25 °C

Procedure:
1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to 100% sodium hydride (0.03 mol, 0.72 g) in dry DMF (30 ml) and stirred at room temperature until the effervescence ceased. 2-Methyl-4-phenyl-5-chloropentan-4-ol (0.01 mol, 2.1 g) in dry DMF (10 ml) was added dropwise at room temperature and then the solution was stirred at 100° for 6 hours. On cooling to room temperature the solution was poured into water to precipitate out a solid which was recrystallised from petroleum (60°-80°)/chloroform giving the title compound (60%) as a white crystalline solid, m.p. 94°-95°.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[CH:24]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[N:2]1([O:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:24]=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=4)[O:27][N:26]=3)=[CH:36][CH:35]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: On1nnc2ccccc21
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 90.9 %

Procedure:
To a solution of 1-hydroxybenzotriazole (244 mg) and 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (528 mg) in dichloromethane (10 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD•HCl) (430 mg) and the mixture was stirred for 4.5 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[5-(4-pentyloxyphenyl)isooxazol-3-yl]benzoic acid benzotriazol-1-yl ester (640 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[C:16]#[C:17][S:18][CH2:19][C@@H:20]([O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[CH3:44].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[C:16]#[C:17][S:18][CH2:19][C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[CH3:44]
Reactant: COC(=O)C[C@@H](CSC#Cc1c(C)cc(C)cc1-c1ccc(F)c(C)c1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)CSC#Cc1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of (S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-(t-butyldiphenylsilyloxy)butanoic acid, methyl ester (1.2 g, 1.9 mM) in dry tetrahydrofuran (10 ml) was treated with glacial acetic acid (0.43 ml, 7.70 mM, 4.0 eq) followed by a 1.0M tetrabutylammonium fluoride solution in tetrahydrofuran (5.78 ml, 5.78 mM, 3.0 eq) and the dark reaction mixture stirred overnight at room temperature under argon. The mixture was diluted with 10 ml of ice water and extracted with ethyl acetate (2×). The organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to give a dark oily residue. The crude oil was purified by flash chromatography (Merck Silica gel, 20% ethyl acetate/hexane) affording the title compound as a dark oil (0.53 g, 71.6%).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[NH:6])[CH3:3].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[CH2:8]1[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=[N:11][N:7]1[C:5](=[N:6][S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[NH:4][CH2:2][CH3:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine hydrochloride (60 g, 260.08 mmol; isolated from reaction of N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine, synthesized as described in WO 2009/115515, with HCl in isopropanol) was dissolved in 1000 mL dichloromethane, and 4-acetylamino-benzenesulfonyl chloride (60.7 g, 260.08 mmol) was added. Under mechanical stirring, triethylamine (131.6 g, 1300.4 mmol) was added over a period of 20 minutes, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water (250 mL) and the organic phase was concentrated under reduced pressure (40° C., 600 mbar). The oily residue was coevaporated twice with 96% ethanol (250 mL) and taken up in 500 mL dichloromethane. The organic phase was extracted with 1N aqueous HCl (75 mL) and subsequently twice with water (200 mL) and evaporated to dryness under reduced pressure to yield 78 g (199.2 mmol, 77%) of N-(4-{[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]sulfamoyl}-phenyl)-acetamide. 1H NMR identical to spectrum obtained from material prepared via novel route (vide supra).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH3:16])=[N:13]2)=[CH:8][CH:7]=1.[Se](=O)=[O:18]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH:16]=[O:18])=[N:13]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2ccc(C)nc2c1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1ccc2ccc(C=O)nc2c1
Yield: 68.3 %

Procedure:
To a solution of 7-(2-methoxyethoxy)-2-methylquinoline (0.16 g, 0.76 mmol) in dioxane (15 mL) and water (0.15 mL) was added selenium dioxide (0.10 g, 0.91 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.12 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][C:6]=2[CH:15]=1
Reactant: COC(=O)C1=Cc2cc(Cl)ccc2OC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1COc2ccc(Cl)cc2C1
Reaction time: 8 h

Procedure:
700 mg of 6B was dissolved in 75 ml of ethyl acetate and the solution was treated with hydrogen (initial pressure of 30 psig), in the presence of a 10% palladium-on-carbon catalyst, for 8 hours. The reaction mixture then was filtered and stripped of solvent to give methyl 6-chloro-3,4-dihydro-2H-1-benzopyran-3-carboxylate (6C), as a yellow liquid, boiling point not determined.
Reaction SMILES: [NH4+:1].[Cl-].C([O:5][C:6]([C:8]1[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=1)=O)C>[OH-].[NH4+]>[CH3:13][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]([NH2:1])=[O:5]
Reactant: [NH4+]
Reactant: CCOC(=O)c1nccn1C
Agent: [Cl-]
Agent: [OH-]
Product: Cn1ccnc1C(N)=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 1969.4 %

Procedure:
NH4Cl (0.150 g, 2.8 mmol) is added to a solution of 1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (15.5 g, 101 mmol) in ammonium hydroxide 35% (112 mL) and the reaction is stirred for 6 h at 100° C. in a sealed reaction flask. The reaction is cooled to 0° C. and the solid formed filtered and washed with ice water and ether to give 1-methyl-1H-imidazole-2-carboxylic acid amide as brown crystals (6.9 g, 55%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[NH2:13][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:24]([O:26][CH3:27])=[O:25])[CH2:9]2)=[CH:7][C:2]=1[Br:1]
Reactant: Nc1ncc(C2CCNC2)cc1Br
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(pyrrolidin-3-yl)pyridin-2-amine, (20 mg, 0.083 mmol) in DCM in ice bath was added DIEA (43.3 μl, 0.248 mmol) and methyl chloroformate (6.40 μl, 0.083 mmol). The reaction mixture was stirred in ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine, dried over sodium sulfate, filtered off, and evaporated. The crude product was used for next step without purification. LCMS (m/z): 300.0, 302.0 (MH+), 0.421 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[NH2:13].[C:14]1([C:20]2[N:21]=[C:22]([CH2:31]Br)[O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]1([C:20]2[N:21]=[C:22]([CH2:31][NH:13][CH:8]3[C:9]4[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)[O:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2c1CCCC2N
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 76.5 %

Procedure:
A solution of 1,2,3,4-tetrahydro-5-methoxy-1-naphthalenamine (0.34 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.50 g) and potassium carbonate (0.60 g) in DMF (7 ml) was stirred for 5 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.50 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)(=O)=O.[CH3:30][C:31]1([CH3:44])[O:36][CH2:35][CH:34]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH2:33][O:32]1>CN(C=O)C>[CH3:30][C:31]1([CH3:44])[O:32][CH2:33][CH:34]([C:37]2[CH:42]=[CH:41][C:40]([O:11][CH2:12][C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]5[N:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:20][CH2:19]4)[S:16][CH:17]=3)=[CH:39][CH:38]=2)[CH2:35][O:36]1
Reactant: CC1(C)OCC(c2ccc(O)cc2)CO1
Reactant: CS(=O)(=O)OCc1csc(C2CCN(c3ncccn3)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(c2ccc(OCc3csc(C4CCN(c5ncccn5)CC4)n3)cc2)CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 114.8 %

Procedure:
Cesium carbonate (735 mg, 0.0022 moles) was added to a solution of (2-(1-(pyrimidin-2-yl)piperidin-4-yl)thiazol-4-yl)methyl methanesulfonate (490 gm, 0.00112 moles) and 4-(2,2-dimethyl-1,3-dioxan-5-yl)phenol (281 mg, 0.001384 moles) in DMF (10 ml) and the reaction mixture was stirred at 60° C. for 2 hours. Then the reaction mixture was then poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product so obtained was purified by column chromatography (silica gel) using 22% ethyl acetate in hexane as eluent to obtain 600 mg product as white solid.
Reaction SMILES: CC(O)(C)C.[CH3:6][O:7][C:8]([CH3:13])=[CH:9][C:10](=O)[CH3:11].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[C:17]([CH3:18])[C:16]2[C:10]([CH:9]=1)=[CH:11][CH:19]=[CH:20][CH:15]=2
Reactant: COC(C)=CC(C)=O
Reactant: Brc1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1cc(C)c2ccccc2c1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
A solution of t-BuOH (44.5 g, 600 mmol) in dry THF (240 mL) was added dropwise to a suspension of NaNH2 (84.4 g, 2.2 mmol) in dry THF (480 mL) under nitrogen. The resulting mixture was heated for 2 h at 40-45° C. After the mixture was cooled, a solution of 4-methoxypent-3-en-2-one (68.5 g, 600 mmol) in dry THF (480 mL) was added dropwise at 30-40° C. The resulting mixture was stirred at 45° C. for 2 h. A solution of bromobenzene (47.1 g, 300 mmol) in dry THF (240 mL) was added and the mixture was stirred at 55° C. for 6 h. The mixture was allowed to cool to room temperature overnight. The mixture was poured into ice, acidified with an aqueous 3 M HCl solution to pH 4-5 and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, and the residue was diluted with acetone (480 mL) and stirred with conc. HCl solution (24 mL) for 10 min. The mixture was diluted with EtOAc (200 mL) and washed with saturated brine (200 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash chromatography (700 g silica gel with dry-loading, eluting by 2% EtOAc in heptanes to give orange oil (19 g, yield: 37%).