Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=1[O:23][CH3:24].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:13][C:12]=2[O:23][CH3:24])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCCNC(=O)c1ccc(N)c(OC)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(Nc2nc(Cl)ncc2Cl)c(OC)c1

Procedure:
2,4,5-Trichloropyrimidine (1.0 g, 5.4 mmol), 4-amino-3-methoxy-N-propylbenzamide (778 mg, 3.74 mmol), and N,N-diisopropylethylamine (1.19 g, 9.21 mmol) were combined in isopropanol (40 mL) and reacted in a microwave (120° C.) for 5½ hours. The 4-(2,5-dichloropyrimidin-4-ylamino)-3-methoxy-N-propylbenzamide that formed as a yellow solid (1.33 g, 71%) was isolated by filtration. A small amount of this material (50 mg, 0.10 mmol) was combined with 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (35 mg, 0.14 mmol) and 10-camphorsulfonic acid (36 mg, 0.15 mmol) in isopropanol (3 mL) to which had been added 0.05 mL water. The mixture was heated in a microwave (130° C.) for 3 hours and on cooling was concentrated. The organics were extracted into dichloromethane which was washed with saturated sodium bicarbonate solution and subsequently dried (sodium sulfate). Concentration followed by ISCO chromatography (gradient elution: 1 to 10% MeOH:dichloromethane) afforded 4-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-methoxy-N-propyl-benzamide as a white solid (58 mg, 70%). Mp: 193-7° C. (dec). LCMS (m/e) 565 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.58 (d, J=8 Hz, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 7.10 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.11 (m, 1H), 4.03 (s, 3H), 3.72 (m, 4H), 3.48 (m, 2H), 2.86 (m, 2H), 2.70 (m, 2H), 2.57 (s, 4H), 2.10 (m, 2H), 1.68 (m, 3H), 1.47 (m, 2H), 1.03 (t. J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20](Cl)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)CO.CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=4)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Solvent: OCCO
Solvent: CS(C)=O
Product: Oc1ccc(Nc2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(Cc5ccccc5)CC4)c3n2)cc1
Yield: 28.4 %

Procedure:
50 mg (0.11 mmol) of 1-(1-benzylpiperidin-4-yl)-6-chloro-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine was dissolved in 1 mL ethylene glycol. 0.24 mmol (26.2 mg) 4-aminophenol was added and the mixture was heated under microwave irradiation to 220 C (15 min). The mixture was diluted with 1 mL DMSO and purified by HPLC (TFA buffers) to give 16 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:24][CH:23]([C:25]([OH:27])=O)[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C1C=C[C:35]2N(O)N=[N:38][C:36]=2[CH:37]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1(N)CC1>CN(C=O)C>[CH:36]1([NH:38][C:25]([CH:23]2[CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)([C:28]([F:30])([F:31])[F:29])[O:14][N:13]=4)=[CH:16][CH:17]=3)[CH2:24]2)=[O:27])[CH2:37][CH2:35]1
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 12, 0.1 g, 0.203 mmol) in DMF (3 mL) was added HOBt (0.027 g, 0.203 mmol), DIPEA (0.052 g, 0.406 mmol), EDCl.HCl (0.058 g, 0.304 mmol) and cyclopropyl amine (0.011 g, 0.203 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). Combined organic layer was washed with saturated NaHCO3 (2×50 mL), water (2×50 mL), brine (50 mL), dried over sodium sulphate and evaporated in vacuo to crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1.1% methanol in DCM to afford white solid (0.036 g, 33%). 1H-NMR (400 MHz, CDCl3) δ: 0.49-0.53 (m, 2H), 0.77-0.87 (m, 2H), 2.74-2.77 (m, 1H), 3.31-3.34 (m, 1H), 3.61 (d, 1H, J=16.88 Hz), 4.01-4.07 (m, 5H), 5.72 (bs, 1H), 6.40 (d, 2H, J=8.68 Hz), 7.47 (d, 2H, J=8.68 Hz), 7.63 (s, 2H). LC-MS (m/z): [M−H] 529.70.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1cccc2ccccc12

Procedure:
To a solution of 18.8 g. of 2-(1-naphthyloxy)ethanol and 15.1 g. of triethylamine in 425 ml. of dichloromethane is added 12.6 g. of methanesulfonyl chloride as described in Example 2 to give the product.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20]C(C)C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1[CH2:38][CH2:37][CH2:36][CH2:35]1>O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][CH2:35][CH2:36][CH2:37][CH3:38])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: C1CCOC1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CCCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.081 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.99 Hz, 3 H) 1.34 (m, 4 H) 1.53 (m, 2 H) 3.01 (t, J=6.62 Hz, 2 H) 6.64 (s, 1 H) 7.43 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.72 Hz, 1 H) 7.64 (d, J=8.09 Hz, 1 H) 7.78 (t, J=7.91 Hz, 1 H) 7.93 (d, J=8.09 Hz, 1 H) 8.35 (d, J=5.52 Hz, 1 H) 14.21 (s, 1 H) 14.81 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c2c1CCCC2
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(S(N)(=O)=O)c2c1CCCC2
Yield: 95.7 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-8-nitro-5-naphthalenesulfonamide (3.1 g, 12 mmol) in 150 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over Raney-Ni. After the theoretical absorption, the reaction mixture was filtered and concentrated to dryness to give 2.6 g (95%) of the title compound. M.p. 216°-219° C. (ethanol); 1H-NMR (DMSO-d6): 1.50-1.93 (m, 4H, 2CH2), 2.17-2.57 (m, 2H, CH2), 2.83-3.17 (m, 2H, CH2), 5.29 (broad s, 2H, NH2), 6.38 (d,J =9Hz, 1H, ArH), 6.75 (broad s, 1H, SO2NH2), 7.35 (d,J =9Hz, 1H, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[S:31][C:30]([CH2:32]O)=[CH:29][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:26][C:27]1[S:31][C:30]([CH2:32][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(Cl)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloro-2-thienyl)methanol (88 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (EtOAc/MeOH), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from IPE-IPA to give the title compound (29.1 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N#Cc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#N)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyanopyridine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].CN1CCCC1=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](F)=[C:24]([CH3:29])[C:23]=1[Cl:30]>O1CCCC1.O>[ClH:21].[Cl:30][C:23]1[C:24]([CH3:29])=[C:25]([CH:26]=[CH:27][C:22]=1[Cl:21])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: Cc1c(F)ccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(OC2CCNCC2)ccc(Cl)c1Cl
Product: Cl
Temperature: 67 °C
Reaction time: 0.17 h
Yield: 150.4 %

Procedure:
4-Hydroxypiperidine (32.5 g) and potassium tert-butoxide (62.7 g) were added to a 1 L jacketed vessel. Tetrahydrofuran (275 mL) was added followed by N-methylpyrrolidone (25 mL). 1,2-Dichloro-4-fluoro-3-methylbenzene (50 g) in tetrahydrofuran (100 mL) was then added, followed by tetrahydrofuran (100 mL). The mixture was heated to 67° C. overnight then cooled to 50° C. Water (250 mL) was added and the mixture was stirred for 10 min at 50° C. The layers were separated and the heating was removed. The organic layer was washed with twice with 10% w/w brine (250 mL). The organic layer was heated to remove solvent by distillation firstly at atmospheric pressure and then under vacuum (400 mbar) whilst isopropanol (950 mL) was added until the tetrahydrofuran was replaced by isopropanol. The solution was then heated to 50° C. Hydrogen chloride in isopropanol (5.5M, 125 mL) was added, an exotherm to 60° C. was observed and the solution was cooled to 50° C. The mixture was cooled from 50° C. to 10° C. over 1 h and then stirred overnight at 10° C. The product was collected by filtration, washed with isopropanol (50 mL) and dried under vacuum at 40° C. to give 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine hydrochloride as an off-white solid (62.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10]C)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:22]1([C:28]#[C:29][C:30]([O:32]CC)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S(=O)(=O)(O)O.[C:40]1(C)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][C:30](=[O:32])[C:29]([CH3:40])=[C:28]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CCC(=Nc1ccc(F)cc1)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(-c2ccccc2)n(-c2ccc(F)cc2)c(-c2ccccc2)cc1=O

Procedure:
To 300 ml of toluene were added 9.1 g (0.040 mole) of N-(4-fluorophenyl)-1-phenylpropaneimine, 4.7 g (0.035 mole) of aluminum chloride and 5.2 g (0.030 mole) of ethyl phenylpropiolate, followed by refluxing the resultant mixture for 5 hours. Thereafter, the reaction mixture was poured into 500 ml of 2N sulfuric acid which had been ice-cooled, followed by extraction with chloroform. After washing the organic layer with water, the organic layer wad dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: 1:50 mixed solvent of methanol and chloroform). The resultant crystals were recrystallized from a 1:1 mixed solvent of acetone and hexane to give 1.0 g of 1-(4-fluorophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 256°-259° C.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=3)[C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(C2(O)CCC(C)(C)c3ccc(Br)cc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Temperature: 25 °C

Procedure:
A flask equipped with a Dean-Stark trap was charged with 3.4 g of (9.85 mmol) of 1,2,3,4-tetrahydro-1-hydroxy-1-(4-methylphenyl)-4,4-dimethyl-7-bromonaphthalene (Compound C) and 40 ml of benzene. A catalytic amount of p-toluenesulfonic acid monohydrate was added and the resulting solution heated to reflux for 2 hours. Upon cooling to room temperature, Et2O was added and the solution washed with H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl then dried over MgSO4. Removal of the solvents under reduced pressure, and column chromatography (100% hexane/silica gel) afforded the title compound as a colorless solid. 1H NMR (CDCl3): δ 7.32 (1H, dd, J=2.1, 8.2 Hz), 7.21 (5H, m), 7.15 (1H, d, J=2.1 Hz), 5.98 (1H, t, J=4.7 Hz), 2.40 (3H, s), 2.32 (2H, d, J=4.7 Hz), 1.30 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[O:11][CH3:12].C[Si]([N-:17][Si](C)(C)C)(C)C.[Li+].CC(O)C.Cl>C1COCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:17])=[NH:7])=[C:4]([F:10])[C:3]=1[O:11][CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1c(Cl)ccc(C#N)c1F
Agent: Cl
Agent: [Li+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(C(=N)N)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 156.9 %

Procedure:
4-chloro-2-fluoro-3-methoxybenzonitrile (3.0 g, 16 mmol) was dissolved in 7 mL dry THF and added dropwise to a 1M solution of lithium bis(trimethylsilyl)amide (18 mL, 18 mmol). After stirring at 25° C. for 5 h, the mixture was treated with 25 mL of 2-propanol saturated with gaseous HCl. Upon standing at 5° C. for 18 h, the mixture was diluted with 30 mL ether whereupon the product precipitated. The precipitated product was collected by filtration, washed with ether and dried under vacuum to give the title compound (3.0 g, 78.6% yield): 1H NMR (DMSO-d6) δ 9.70 (br d, 3H), 7.58 (m, 1H), 7.46 (m, 1H), 7.39 (br d, 1H), 3.96 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].FC(F)(F)S(O[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])(=O)=O.CC1C=CC=C(C)N=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH2:11][O:12][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OCc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a 3-L round-bottomed flask was added (3-fluoro-4-nitrophenyl)methanol (4.7 g, 27.5 mmol) and DCM (47 mL). To the mixture was added triisopropylsilyl trifluoromethanesulfonate (9.26 g, 30.2 mmol) and 2,6-dimethylpyridine (3.53 g, 33.0 mmol). The resulting mixture was stirred for 3 hours at RT, and washed with NH4Cl (5-250 mL) and H2O (5-250 mL). The organic layer was collected and dried over sodium sulfate and concentrated to afford (3-fluoro-4-nitrobenzyloxy)triisopropylsilane (8.9 g, 99% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[Cl:12][CH2:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCc1ncccc1F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1cccnc1CCl
Temperature: 0 °C
Yield: 80.5 %

Procedure:
Dissolve (3-fluoro-pyridin-2-yl)-methanol (215 mg, 1.69 mmol) in dichloromethane (10 mL) and cool to 0° C. Add thionyl chloride (160 μL, 2.20 mmol) and stir the reaction for one hour. Add dichloromethane (50 mL) and stir the reaction with saturated aqueous sodium bicarbonate (2×40 mL) and brine (2×40 mL). Separate and dry the organic portion over magnesium sulfate, filter, and concentrate under reduced pressure to provide 198 mg (80%) of product, which is used without further purification. MS: m/z 146, 148 [C6H5ClFN+1]+; 1H NMR (300 MHz, CDCl3): δ 8.41-8.44 (m, 1H), 7.41-7.47 (m, 1H), 7.28-7.34 (m, 1H), 4.75 (d, J=2.0 Hz, 2H); 19F NMR (282 MHz, CDCl3): δ-123.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14](Br)=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[F:32])#[CH:19]>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:14]([C:19]#[C:18][C:20]2[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2[F:32])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1F
Reactant: CC(C)(C)OC(=O)COc1ncc(Cl)cc1Br
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)cnc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 182, starting from tert-butyl[(3-bromo-5-chloropyridin-2-yl)oxy]acetate (Intermediate 183) and 2-ethynyl-1-fluoro-4-(propane-1-sulfonyl)-benzene (Intermediate 109), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:22].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]2=[O:1])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1

Procedure:
The product from Example 87A was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. Then the reaction mixture was concentrated, partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, and concentrated to yield the title compound. MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[Cl:19]C1C(F)=C(B(O)O)C=CC=1>>[Cl:19][C:7]1[C:2]([F:1])=[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1cccc(Cl)c1F
Product: O=C(O)c1csc(-c2cccc(Cl)c2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (3-chloro-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Br:9])=[CH:4][N:3]=1.[NH3:10]>>[Br:9][C:5]1[C:6]([NH2:10])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: N
Product: Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-Dichloro-5-bromopyrimidine (200 g, 0.88 mol) is added slowly to NH3 (1000 ml, 7 M in MeOH) while the reaction mixture is kept below 10° C. The reaction mixture is stirred at rt for 2 h, heated to 60° C. for 2 h, and then cooled again to rt and stirred for 55 h. It is concentrated under reduced pressure, and the residue is suspended in H2O (500 ml). The aqueous layer is extracted with EtOAc (3×) and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1.[OH-].[K+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(-c2ccccc2F)cc1

Procedure:
26.5 g (0.11 mol) of methyl (2′-fluoro[1,1′-biphenyl]-4-yl)acetate are initially charged in 50 ml of ethanol and, at room temperature, admixed with a solution of 12.8 g (0.19 mol) of potassium hydroxide pellets in 25 ml of water. The mixture is then heated under reflux for 4 h. After cooling, the crude mixture is concentrated under reduced pressure, and the residue is dissolved in 100 ml of water and acidified using conc. hydrochloric acid. The precipitate is filtered off and washed repeatedly with water, and the solid is dried. This gives Example VI in the form of white crystals.