Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)(=[O:31])=[O:30]
Reactant: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccn2cc(-c3ccc(C#CCCOS(C)(=O)=O)cc3)nc2c1
Temperature: 10 °C
Yield: 66.4 %

Procedure:
The product of Step B (0.135 g) in dichloromethane (3 mL) was treated with pyridine (0.37 g) and cooled to 10° C. The cold solution was treated with methanesulfonyl chloride (0.112 g) and allowed to stir and warm to ambient temperature over 18 hours. The reaction mixture was washed with 1% H2SO4 solution, saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give the title compound (0.115 g).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([O:16]CC)=O)#[N:2].[CH3:19][NH2:20]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([NH:20][CH3:19])=[O:16])#[N:2]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1C#N
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccn2)c1C#N

Procedure:
To a solution of 2.5 g of 5cyano-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 20 ml of DMF was added an excess of 40% aqueous monomethylamine so as not to precipitate out the pyrazole starting material. Approximately 24 hours later additional monomethylamine was added to the reaction mixture as well as additional DMF so as to keep these reactants in solution. The reaction mixture was heated and subsequently added to 150 ml of ice water. The precipitated solid was collected by filtration and recrystallized from methanol to afford 1.2 g of 5-cyano-1-(2-pyridinyl)-N-methyl-1H-pyrazole-4-carboxamide. mp=200°-202° C.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]1[C:15](=[O:30])O[C:17](=[O:29])[C:18]=1[C:19]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=1)=[C:4]1[CH2:13][CH2:12][CH2:11][CH2:10][N:5]12.C[N:32](C)C=O>N>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:14]1[C:15](=[O:30])[NH:32][C:17](=[O:29])[C:18]=1[C:19]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=1)=[C:4]1[CH2:13][CH2:12][CH2:11][CH2:10][N:5]12
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCCC4)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCCC4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 72 mg of 3-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml of dimethylformamide and 5 ml of 33% aqueous ammonia was heated to 140° C. for 4 hours. The resulting crystals were filtered off and dried to give 50 mg of 3-(6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 286°-289° C.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C@@H:3]([NH:23]C(=O)OC(C)(C)C)[C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]([CH3:32])([CH3:31])[C@H:3]([C:4]([NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH3:22])[CH:15]=2)=[CH:11][CH:12]=1)=[O:5])[NH2:23]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)cn2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)(C)C)cn2)ccc1C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-2,2-dimethyl-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 96, 8.2 mg) in dry dichloromethane (0.5 mL) cooled to 0° C., TFA (57 μl, 0.740 mmol) was added dropwise and the solution was stirred for 3 hours at that temperature. The volatiles were evaporated. The residue was dissolved with dichloromethane (2 mL) and an aqueous saturated solution of NaHCO3 was added (4 mL). The layers were separated and the aqueous layer was extracted twice with dichloromethane. The gathered organic layers were dried over sodium sulphate and evaporated to afford the title compound (6.2 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)#[N:2].[H][H]>N.C(O)C.[Ru]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1
Reactant: [H][H]
Reactant: N#CCCCC1OCCO1
Agent: [Ru]
Agent: N
Solvent: CCO
Product: NCCCCC1OCCO1
Reaction time: 32 h
Yield: 802.4 %

Procedure:
To a solution of 14.5 gm (10.3 mmol) 2-(3-Cyanopropyl)-1,3-dioxolane in anhydrous ammonia and ethanol was added 5% ruthenium on aluminum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 100 p.s.i. at ambient temperature for 32 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 12.0 gm (80.5%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:17]([NH:27]C(=O)OC(C)(C)C)[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[N:5][N:6]2[CH3:35].[F:41][C:42]([F:47])([F:46])[C:43](O)=[O:44].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:17]([NH:27][C:43](=[O:44])[C:42]([F:47])([F:46])[F:41])[CH2:18][C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[N:5][N:6]2[CH3:35]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cccnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cccnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To (S)-tert-butyl (1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (57A, 3.39 g, 5.73 mmol) in DCM (5 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2.5 hours. Upon complete removal of the Boc protecting group, trifluoroacetic anhydride (2.02 mL, 14.31 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was filtered through celite, concentrated in vacuo, taken in EtOAc, and carefully neutralized with 1M aqueous NaHCO3 until the aqueous layer was at pH 10. The organic layer was collected and the aqueous layer extracted once more with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound. MS (m/z) 588.14 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9](Cl)=[O:10].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(CC)CC)C.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:12][CH2:13][CH3:14])[C:9]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:10]
Reactant: CCCN(C(=O)Cl)c1ccccc1Cl
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(C(=O)n1ccnc1)c1ccccc1Cl

Procedure:
of N-2-chlorophenyl-N-propylcarbamoyl chloride, 14g. of imidazole and 30 ml. triethylamine were refluxed in 200 ml. of dry tetrahydrofuran for five hours. The reaction mixture was poured into 2 liters of water and the slurry chilled causing some separation from the aqueous phase. A slightly sticky crystalline solid was collected, washed with water and dried in vacuo. It was recrystallised from a mixture of toluene and light petroleum (62°-68° C. fraction) with charcoaling. On cooling, an oil separated which soon solidified to give the product, 1-(N-2-chlorophenyl-N-propylcarbamoyl)imidazole m.p. 75.5°-76.5° C.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1)#[C:25][CH3:26]>>[F:14][C:10]1([F:13])[CH2:9][CH2:8][C:7]2([C:15]3([N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]3)[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]4[CH:30]=[N:31][CH:32]=[C:27]([C:24]#[C:25][CH3:26])[CH:28]=4)[CH:23]=3)[CH2:6]2)[CH2:12][CH2:11]1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(F)(F)CC1
Product: CC#Cc1cncc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CCC(F)(F)CC2)C3)c1
Yield: 23.9 %

Procedure:
The title compound (26 mg, 24% yield) was prepared as described for Example 28c starting from 6′-bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 27, 100 mg, 0.26 mmol) and 5-(prop-1-ynyl)pyridin-3-ylboronic acid (Intermediate 15, 50.5 mg, 0.31 mmol). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.22-1.30 (m, 1 H), 1.51 (br. s., 2 H), 1.71 (br. s., 1 H), 1.78-1.97 (m, 4 H), 2.09 (s, 3 H), 2.19 (s, 3 H), 3.06 (d, 1 H), 3.15 (d, 1 H), 6.61 (s, 2 H), 6.85 (d, 1 H), 7.41 (d, 1 H), 7.56 (dd, 1 H), 7.91 (t, 1 H), 8.51 (d, 1 H), 8.67 (d, 1 H). MS (APCI+) m/z 419.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=O)[N:9]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=2)=[O:21])[N:9]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Cc1csc(-c2nn(CC(=O)O)c(=O)n2CC(C)C)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(-c2nn(CC(=O)NCc3cccc(C(F)(F)F)c3)c(=O)n2CC(C)C)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.121 mmol) of 2-[3-(3-chloro-4-methyl-2-thienyl)-4-isobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 249A and 23.4 mg (0.133 mmol) of 3-trifluoromethyl-benzylamine are placed in 1.5 ml of DMF and treated with 19.7 mg (0.146 mmol) of HOBt. 30.2 mg (0.158 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with about 15 ml of water and the resulting precipitate filtered off, washed with water and dried in vacuo. 43 mg (73% of theory) of the target compound are thus obtained.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15](=O)[C:14]3=[CH:18][C:19]([CH3:21])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:22]=1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]=[C:15]([Cl:3])[C:14]3=[CH:18][C:19]([CH3:21])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:22]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1NC2=O
Solvent: ClCCl
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Add phosphoryl chloride (1.47 mL, 2.43 g, 15.85 mmoles) to 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (1.117 g, 4.53 mmoles) in DCM (50 mL) and stir at room temperature over a weekend. Add ice water to the reaction mixture then add DCM, separate the aqueous layer and wash the DCM layer with water and sodium hydrogen carbonate solution. Dry the DCM solution with MgSO4, filter and evaporate the solvent in vacuo to give 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.167 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1[Cl:20])([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1[Cl:20]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1-c1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Cl)cc1-c1cc(Cl)c(Cl)cc1Cl
Temperature: 100 °C

Procedure:
2-Amino-2',4,4',5,5'-pentachlorobiphenyl was prepared from 2-Nitro-2',4,4',5,5'-pentachlorobiphenyl (2.5 g, 6.8 mmol) by dissolving the compound in acetic acid (60 mL) heated to 100° C. and adding a solution of SnCl2 (6 g) in concentrated HCl (30 mL). The temperature was raised to reflux for 3 h, then the reaction mixture was allowed to cool to ambient temperature, whereupon it was poured into ice (100 g). The pH of the solution was adjusted to 9 with NaOH and then extracted with methylene chloride (2×100 mL). The extract was washed with NaOH (1N, 2×25 mL) and water (100 mL); dried over MgSO4 and filtered to give the impure amine. The crude product was chromatographed in two equal batches (Chromatotron®, Harrison Research, Palo Alto, Calif., 4 mm silica gel, step gradient from hexanes to 10% ethyl acetate in hexanes, 20 mL/min) to give the title hapten (830 mg). Mass spectrum: m/z at 340 (M+1) for C12H6Cl5N.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(=O)(=O)(O)O>[OH-].[Na+].O1CCCC1>[C:9]([OH:25])(=[O:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)O
Reaction time: 1 h
Yield: 54.7 %

Procedure:
Hydroquinone (55 g) was dissolved in 10% sodium hydroxide solution (200 g) and to the resulting solution was added tetrahydrofuran (50 g). A solution of palmitoyl chloride (13.7 g) in tetrahydrofuran was added dropwise to the mixture over about 1 hour, while maintaining the temperature at 0° to 5° C. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was poured into dil. sulfuric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water and concentrated under a reduced pressure. The concentrate was purified by silica gel column chromatography to give hydroquinone monopalmitate (10 g). m.p. 90.5°-91.5° C.
Reaction SMILES: C(OC(=O)N=NC(OC(C)(C)C)=O)(C)(C)C.[Si:17]([O:34][C@H:35]([CH2:45][CH2:46]O)[C:36]([NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Si:17]([O:34][C@@H:35]1[CH2:45][CH2:46][N:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:36]1=[O:37])([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](O[C@H](CCO)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CCN(c2ccccc2)C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl-N-tert-butoxycarbonyliminocarbamate (2.44 g, 10.61 mmol) in THF (17.25 mL) at 0° C. was added n-tributylphosphine (2.15 g, 2.64 mL, 10.61 mmol) dropwise, the cooling bath was removed and the reaction mixture stirred at RT for 20 min. The reaction mixture was then cooled to 0° C. and a solution of (R)-2-(tert-butyldiphenylsilyloxy)-4-hydroxy-N-phenylbutanamide (1.15 g, 2.65 mmol) in THF (17.25 mL) was added slowly, the cooling bath removed and the reaction mixture stirred at RT for 45 min. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organics were washed with water (2×), brine, dried over MgSO4 and evaporated to dryness. Purification by silica gel chromatography (1-10% EtOAc in hexane) afforded (R)-3-(tert-butyldiphenylsilyloxy)-1-phenylpyrrolidin-2-one (1.1 g, 96%) as an oil. 1H-NMR (400 MHz, DMSO-d6) δ 7.81 (dd, J=1.5, 7.7 Hz, 2H), 7.72-7.66 (m, 4H), 7.51-7.36 (m, 8H), 7.15 (m, 1H), 4.51 (dd, J=8.1, 9.2 Hz, 1H), 3.72-3.59 (m, 2H), 2.26-2.21 (m, 1H), 2.03-1.98 (m, 1H) and 1.06 (s, 9H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=416.7; tR=2.40 min.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[CH2:6]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9][NH:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCO.C(Cl)Cl>[CH2:4]([N:8]1[CH2:7][CH2:6][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1)[CH:3]=[CH2:2]
Reactant: C1CCOC1
Reactant: COC(=O)C1CNCCc2c1[nH]c1ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C=CCBr
Solvent: ClCCl
Solvent: CCO
Product: C=CCN1CCc2c([nH]c3ccccc23)C(C(=O)OC)C1

Procedure:
A 72 L three-necked mechanically stirred round bottomed flask was set up with a reflux condenser. To the flask was charged dry tetrahydrofuran (10 L), and methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (800 g, 3.27 mol). The mixture was stirred, and tetrabutylammonium bromide (21.1 g, 0.06mol), anhydrous potassium carbonate (1.13 kg, 8.8 mol), and allyl bromide (29.7 mL, 396 g, 3.27 mol) were added sequentially in one lot each. After addition, the mixture was stirred at about 20° C. for 2.5 days. The mixture was diluted with (10 L) hexanes, filtered, and transferred to a separatory funnel. The solution was washed with water (2 L), saturated sodium chloride (1 L), dried over sodium sulfate, filtered, then concentrated to a dark green-brown oil (770 g), methyl 3-allyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate, suitably clean to be used in the next synthetic step. Yield =83%. TLC (EtOH/CH2Cl2, 1:9): Rf=0.7; 1H NMR (400 MHz, CDCl3): δ 2.79-2.86 (m, 1H), 2.90-3.09 (m, 4H), 3.28-3.43 (m, 3H), 3.78 (s, 3H), 4.02 (dd, J=1.6, 6.8 Hz, 1H), 5.23 (d, J=10.4 Hz, 1H), 5.27 (dd, J=1.4, 17 Hz, 1H), 5.90-6.00 (m, 1H), 7.11-7.19 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 8.40 (bs, 1H); 13C NMR (100 MHz, CDCl3): δ 24.1, 45.4, 52.2, 55.7, 56.9, 61.4, 110.7, 113.8, 117.5, 118.0, 119.2, 121.4, 128.4, 132.1, 134.7, 135.7, 172.5; melting point: 105-108 ° C. (uncorrected).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([F:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:54](=O)([O-:56])[O-:55].[K+].[K+].Cl>CO.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:54]([OH:56])=[O:55])[N:8]([CH2:11][C:12]([F:15])([CH3:14])[CH3:13])[N:7]=[CH:6]2
Reactant: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Temperature: 60 °C
Yield: 48.4 %

Procedure:
6-Bromo-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole (1.64 g, 4.11 mmol) was dissolved in 9:1 methanol/water degassed with carbon monoxide (27 mL). To this was added 1-((3-(diphenylphosphino)propyl)(phenyl)phosphino)benzene (85 mg, 0.21 mmol), palladium (II) acetate (46 mg, 0.21 mmol), and potassium carbonate (1.70 g, 12.3 mmol). The reaction mixture was heated to 60° C. for 20 hours. The reaction mixture was then acidified to pH 1 by the addition of 5M hydrochloric acid, and the crude reaction mixture was partitioned between ether and water. The aqueous layer was extracted with ether, and the combined organic layers were washed with brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a silica gel column, eluting with a gradient of 0.2-10% methanol/dichloromethane to yield 5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid (7a) (724 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH2:15](O)[CH3:16]>>[Cl:1][C:2]1[C:3]([C:8]([O:10][CH2:15][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1ncccc1Cl
Agent: FB(F)F
Product: CCOC(=O)c1ncccc1Cl

Procedure:
3-Chloropicolinic acid is esterified using boron trifluoride and ethanol by the procedure described in Example 1 to give ethyl 3-chloropicolinate.
Reaction SMILES: I[CH:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[C:26]#[CH:27])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>ClCCl.C(O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[C:26]#[C:27][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:9])=[CH:4][CH:5]=3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: OC(I)c1ccccc1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2ccc(NC(=O)C#Cc3ccc(CO)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.a. from iodobenzyl alcohol and propynoic acid-(4′-methoxybiphenyl-4-yl)amide. Yield: 0.21 g (22.9% of theory); C23H19NO3 (M=357.41); calc.: molecular ion peak (M+H)+: 358; found: molecular ion peak (M+H)+: 358; Rf value: 0.35 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[CH:9]=1.C1C(=O)N([I:41])C(=O)C1>CC#N>[CH3:29][Si:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][O:25][CH2:24][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:33])([CH3:32])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:41])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(I)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (775 mg, 1.58 mmol) in CH3CN (10 mL) was added NIS (391 mg, 1.74 mmol). The resulting solution was stirred at rt for 30 min before quenching with Na2S2O3 (sat.). CH3CN was removed under reduced pressure. The residue was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-20% EtOAc/Hexanes, Rf=0.3 in 20% EtOAc) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow oil (751 mg).