Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:28]3[CH:27]=[CH:26][C:25]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:24]([F:23])[CH:29]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccc(-c4ccccc4)c(F)c3)o2)c1
Temperature: 85 °C

Procedure:
The furyl bromide (99)(100 mg, 0.28 mmol) was coupled to 2-Fluoro-biphenyl-4-boronic acid (65 mg, 0.30 mmol) acid using Method E, except that the reaction was heated at 85° C. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[CH3:2].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]([NH:20][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Reactant: CCOc1cc2c(Oc3cccc(N)c3)ncnc2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
To a stirred solution of 3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)aniline (100 mg, 0.322 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (151 mg, 0.482 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (48 mg, 28%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (brs, 1H), 9.01 (s, 1H), 8.55 (s, 1H), 7.54-7.59 (m, 2H), 7.37-7.43 (m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 6.87 (s, 1H), 4.24 (q, J=7 Hz, 2H), 4.00 (s, 3H), 1.53 (s, 6H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 532 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:32][C:33]([NH2:35])=[O:34].O>CN(C=O)C>[NH2:35][C:33](=[O:34])[CH2:32][N:13]1[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14]1
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)nc1
Reactant: NC(=O)CBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=CN(CC(N)=O)C(NS(=O)(=O)c2ccc(C)cc2)C=C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 1B was prepared starting from compound 1A in three steps following an analogous method to that described in U.S. Pat. No. 6,358,971, which is incorporated by reference herein in its entirety. Specifically, a mixture of methyl 6-aminonicotinate (1A, 3 g, 19.7 mmol) and tosylchloride (4.5 g, 23.6 mmol) in pyridine (40 mL) was heated at 80° C. for 16 hrs. The reaction was cooled to room temperature and pyridine was removed in vacuo. The resulting residue was diluted with water and allowed to stir for 10 min. The resulting solid was filtered and dried under vacuum to provide methyl 6-(4-methylphenylsulfonamido)nicotinate which was used without further purification. To a suspension of methyl 6-(4-methylphenylsulfonamido)nicotinate (5.3 g, 17.3 mmol) in anhydrous DMF was sequentially added DIEA (3.31 mL, 19.03 mmol) and then 2-bromoacetamide (2.63 g, 19.03 mmol). The reaction was stirred at ambient temperature for 24 hrs and then poured into water. The resulting solid was filtered and dried under vacuum to provide methyl 1-(2-amino-2-oxoethyl)-6-(4-methylphenylsulfonamido)-1,6-dihydropyridine-3-carboxylate which was used without further purification. To a suspension of methyl 1-(2-amino-2-oxoethyl)-6-(4-methylphenylsulfonamido)-1,6-dihydropyridine-3-carboxylate (1.0 g, 2.8 mmol) in DCM (20 mL) was added TFAA (8.0 mL, 57.5 mmol) dropwise at ambient temperature. The reaction was refluxed for 2 hrs, cooled to ambient temperature, and then concentrated in vacuo. The resulting residue was suspended in saturated sodium bicarbonate and stirred for 15 min. The resulting solid was filtered and dried under vacuum to provide methyl 2-(2,2,2-trifluoroacetamido)imidazo[1,2-a]pyridine-6-carboxylate (1B) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][CH:15]([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>C(O)C>[F:14][CH:15]([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:22]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC(F)F)cc3)cs2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A mixture of methyl 4-thiocarbamoylbenzoate (1.56 g), 4-difluoromethoxyphenacyl bromide (2.65 g) and ethanol (15 ml) was stirred at 80 to 90° C. for 1 hour. The reaction mixture was cooled, and precipitated crystals were collected by filtration to obtain methyl 4-[4-(4-difluoromethoxyphenyl)-2-thiazolyl]benzoate (2.00 g, yield: 69%). The product was recrystallized from ethanol to obtain pale yellow prisms. Melting Point: 146 to 148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(Cl)c5)c4)c3c2)c1
Yield: 17.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (90 mg, 0.14 mmol) was hydrolyzed with lithium hydroxide (18 mg, 0.42 mmol) in THF/water/methanol (1/0.5/1 ml) mixture to afford 12 mg (18% yield) of the pure product after purification by preparative TLC (Silicagel-1000 micron) using 10% ethyl acetate in hexane as eluent. 1H NMR (DMSO-d6, 400 MHz): δ 11.83 (s, 1H), 9.85 (s, 1H), 8.48-8.47 (d, 1H), 8.43 (s, 1H), 8.346-8.342 (d, 1H), 7.90 (s, 1H), 7.80-7.79 (d, 1H), 7.51-7.25 (m, 8H), 5.40 (s, 2H), 3.06 (s, 3H). MS: m/z=478.2 (M+1), HPLC: 92.01% (method B).
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].C([O-])(O)=O.[Na+].[ClH:32].CCOCC>Cl>[ClH:32].[ClH:32].[Cl:32][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CCOCC
Product: Clc1ccc(N2CC3CCC(C2)N3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
The product from Example 11A (0.03 g; 0.103 mmol) in 12M HCl (0.13 mL) was treated with sodium nitrite (10 mg, 0.129 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stir overnight. The mixture was neutralized by addition of NaHCO3 and then extracted with CH2Cl2. The extracts were dried (Na2SO4), concentrated under reduced pressure, and the residue purified on SiO2 (10% MeOH/CH2Cl2/1% NH4OH) to provide the free base. The free base was treated with 1M HCl/ether to provide the title compound (43% yield). 1H NMR free base (CDCl3, 300 MHz) δ 1.8 (m, 4H), 2.1 (br s, 1H, exchangeable), 3.0 (d.K=11 Hz, 2H), 3.4-3.7 (br s, 2H), 7.0-7.2 (m, 2H0, 7.9 (m, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:12]([CH2:13][C:14]#[CH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:18]([N:25]=[N+:26]=[N-:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].O.C(O)(C)(C)C>[CH2:18]([N:25]1[CH:15]=[C:14]([CH2:13][C@@H:12]2[C@@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:9][C:10]([CH3:16])([CH3:17])[O:11]2)[N:27]=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CC[C@H]1OC(C)(C)O[C@@H]1CCCCCCC
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1cn(Cc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (4R,5R)-4-heptyl-2,2-dimethyl-5-(prop-2-ynyl)-1,3-dioxolane (14 mg, 0.059 mmol) in a water/t-butanol mixture (0.11, 0.11 mL), was added benzyl azide (8.5 μL, 1.1 eq), copper sulfate (56 μL of a 0.1 M sol'n, 0.1 eq), and sodium ascorbate (56 μL of a 1 M sol'n, 1 eq). The mixture was stirred at room temperature overnight to yield the title compound (21.1 mg, 97%). 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 3H), 7.25 (m, 2H), 5.54 (d, 14.7 Hz, 1H), 5.45 (d, 14.7 Hz, 1H), 3.86 (m, 1H), 3.64 (m, 1H), 3.03 (dd, 4.2 Hz, 15.3 Hz, 1H), 2.92 (dd, 6.9 Hz, 15.3 Hz, 1H), 1.55-1.23 (m, 12H), 1.26 (s, 3H), 1.23 (s, 3H), 0.87 (t, 6.8 Hz, 3H). LRMS (APCI+) found 372.5, [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:26]5[CH:25]=[N:24][C:33]6[C:28]([CH:27]=5)=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1cnc2ccccc2c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5ccccc5c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 3-quinolineboronic acid (Aldrich, Buchs, Switzerland, 22 mg, 0.127 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.40 min (Method A); M+H=421 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.03-8.96 (m, 2H), 8.52 (s, 1H), 8.21-7.99 (m, 5H), 7.83-7.76 (m, 1H), 7.75-7.71 (m, 1H), 7.71-7.65 (m, 1H), 3.95 (s, 3H), 3.59 (s, 3H), 1.98 (s, 3H))
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:25][C@@H:26]1[CH2:30][NH:29][CH2:28][C@H:27]1[NH:31]C(=O)OC(C)(C)C>>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[N:29]1[CH2:30][C@@H:26]([F:25])[C@H:27]([NH2:31])[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1F
Reactant: O=S1CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Product: N[C@@H]1CN(c2cc(N3CCS(=O)c4ccccc4C3)nc3ccc(Cl)cc23)C[C@H]1F

Procedure:
The title compound was prepared in analogy to Example 19-1 in Scheme 7 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1) and tert-butyl (trans-4-fluoropyrrolidin-3-yl)carbamate. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, J=2.27 Hz, 1 H), 7.78-7.68 (m, 2 H), 7.55 (dd, J=9.09, 1.52 Hz, 1 H), 7.52-7.42 (m, 2 H), 7.39 (dd, J=9.09, 2.27 Hz, 1 H), 6.28-6.21 (m, 1 H), 5.25 (d, J=15.66 Hz, 1 H), 5.10-4.95 (m, 1 H), 4.90-4.54 (m, 2 H), 4.65-4.40 (m, 1 H), 4.30-4.10 (m, 1 H), 4.05-3.59 (m, 1 H), 3.55-3.51 (m, 2 H), 3.40-3.35 (m, 3 H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cu](C#N)[C:12]#[N:13].O>CN(C=O)C>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-3-nitropyridine (5 g, 31.6 mmol, 1.0 eq.) in 50 mL of DMF was added copper cyanide (2.47 g, 38 mmol, 1.2 eq.) and the reaction heated to 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into 100 mL of water. The mixture was extracted with ethyl acetate (3×50 mL) and the combined ethyl acetate portions were dried over soduim sulfate and concentrated. The crude material was chromatographed on silica with 3:7 ethyl acetate/hexanes to give 2-cyano-3-nitropyridine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][NH:21][C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23].[H-].[Na+].[CH3:33]I>>[CH3:33][N:21]([CH2:20][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[C:2]=1[CH3:1])[C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23]
Reactant: Cc1c(CNC(=O)c2ncccc2Cl)cncc1-c1ccc2c(c1)CCC(=O)N2C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cc1c(CN(C)C(=O)c2ncccc2Cl)cncc1-c1ccc2c(c1)CCC(=O)N2C

Procedure:
In analogy to the procedure described for the preparation of example 195, 3-chloro-pyridine-2-carboxylic acid [4-methyl-5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 224) has been reacted with sodium hydride and methyl iodide to give the title compound as light brown amorphous solid. MS: 435.5 (M+H+).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:13]=2)=[CH:4][N:3]=1.[NH2:23][NH2:24]>CC(O)C.O>[F:8][C:7]1[C:2]([NH:23][NH2:24])=[N:3][CH:4]=[C:5]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:13]=2)[CH:6]=1
Reactant: Fc1cc(-c2cnn(CCOC3CCCCO3)c2)cnc1F
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: NNc1ncc(-c2cnn(CCOC3CCCCO3)c2)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 2,3-difluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine (3.0 g, 9.5 mmol) in IPA (47.7 mL, 0.2 M) at room temperature was added hydrazine (3.6 mL, 114.4 mmol). The reaction mixture was stirred at 60° C. for 2 h, at which point the reaction was cooled to room temperature and concentrated in vacuo. The concentrated material was suspended in saturated NaHCO3 solution and filtered to obtain product as a white, fluffy solid. The material was re-suspended in water (30 mL), filtered, and dried under high vacuum to obtain 1-(3-fluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (2.2 g, 72% yield) as an orange solid. MS m/z=322.2 [M+1]+. Calc'd for C15H20FN5O2: 321.4.
Reaction SMILES: [I-:1].[K+].F[B-](F)(F)F.[Cl:8][C:9]1[CH:10]=[C:11]([N+]#N)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18]>CC(C)=O>[Cl:8][C:9]1[C:14]([O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[N:13][CH:12]=[C:11]([I:1])[CH:10]=1
Reactant: N#[N+]c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Reactant: [I-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)C(Oc1ncc(I)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium iodide (421 mg, 2.53 mmol) was added to a solution of 5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridine-3-diazonium tetra fluoroborate (Preparation 53, 200 mg, 0.51 mmol) in acetone (10 mL). The mixture was stirred for 15 minutes at room temperature then concentrated in vacuo. The resulting crude residue was partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc. The combined organics were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 10% diethyl ether in heptane to afford the title compound as an orange oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4][C:3]1=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1C=CC=CC=1.C(Cl)Cl.O>[CH2:11]([NH:18][C@H:3]1[C@@H:2]([CH3:1])[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CC1CCC2(CC2)CC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H]1CCC2(CC2)C[C@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
Racemic 6-methyl-spiro[2.5]octan-5-one (0.92 g, 6.656 mmol) and benzylamine (0.76 mL, 6.989 mmol) were dissolved in benzene (6 mL) and stirred at reflux with continuous removal of H2O for 3 hours. The reaction mixture was allowed to cool to RT and was diluted with DCM (30 mL). The yellow solution was cooled to 0° C. Sodium triacetoxyborohydride (95%, 1.78 g, 7.988 mmol) and acetic acid (0.5 mL, 8.65 mmol) were added. After about 20 minutes, the ice bath was removed and the suspension stirred at RT overnight. The reaction mixture was cooled to 0° C. and quenched by addition of saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed once more with saturated aqueous NaHCO3, dried (Na2SO4), filtered and evaporated. The remaining yellow oil was purified by SiO2 chromatography (100 g SiO2, DCM/(DCM:MeOH:NH4OH 60:10:1) 100 to 85% DCM) to give 0.92 g of racemic cis benzyl-(6-methyl-spiro[2.5]oct-5-yl)-amine as a light brown oil (yield 60%).
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 3-{[(4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (19.7 g) synthesized in Example A64(1) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/ethanol (500/500), flow rate: 60 mL/min, column temperature: room temperature). The fraction containing an optically active form having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (8.95 g, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (100 mL) and tetrahydrofuran (100 mL) was added 1N aqueous sodium hydroxide solution (30 mL), and the mixture was stirred at room temperature for 3 hr and concentrated under reduced pressure. The residue was dissolved in water (200 mL), and 1N hydrochloric acid (35 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (8.06 g, 43%, 99.9% ee) as a white solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:43]1[N:44]=[C:45]([CH3:49])[N:46]([CH3:48])[CH:47]=1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:7]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:43]3[N:44]=[C:45]([CH3:49])[N:46]([CH3:48])[CH:47]=3)[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C1CCCCC1)OC
Reactant: Cc1nc(Br)cn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cn(C)c(C)n2)c1)C1CCCCC1)OC
Temperature: 120 °C

Procedure:
N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethoxy)propanamide [Example 34 Step i)] (360 mg), potassium carbonate (203 mg), Pd(Ph3P)4 (42.5 mg) and 4-bromo-1,2-dimethyl-1H-imidazole (193 mg) in MeOH (3 mL) was loaded into a microwave vial, flushed with nitrogen and sealed. The reaction mixture was heated within a Discover microwave at 120° C. for 20 min. After cooling, the mixture was filtered and the filtrate was washed with DCM. Volatiles removed and the residue was purified on silica using 50%-100% EtOAc/iso hexane and then 5% MeOH/DCM to afford the subtitled compound (250 mg). MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.61 and 7.59 (2×s, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.28-7.21 (m, 1H), 7.10-7.03 (m, 2H), 4.62 and 4.37 (2×t, J=5.1 Hz, 1H), 4.26-4.17 and 3.62-3.52 (2×m, 1H), 3.82-3.74 (m, 2H), 3.73-3.64 (m, 2H), 3.60 (s, 3H), 3.41 (s, 3H), 3.38 (s, 3H), 3.37 and 3.29 (2×d, J=4.7 Hz, 2H), 2.94-2.86 (m, 2H), 2.73-2.65 (m, 2H), 2.43 (s, 3H), 1.85-1.73 (m, 2H), 1.73-1.60 (m, 3H), 1.54-1.22 (m, 4H), 1.15-1.01 (m, 1H); a ˜2:1 mixture of rotamers is observed.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][N:3]=1.[NH2:19][NH2:20]>C1COCC1>[NH:19]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][N:3]=1)[NH2:20]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)nc1-c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1-c1ccccc1
Yield: 91 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-phenylpyrimidine-5-carboxylate (0.09 g, 0.34 mmol) and hydrazine (0.06 g, 1.7 mmol) in THF resulting in a 91% yield (0.08 g); m.p. 74-75° C.