Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[N:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C@@H:27]2[CH2:26][CH2:25][C@H:24]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:12]=[N:13][C:14]([O:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:15][CH:16]=4)=[N:9]3)[CH2:29][CH2:28]2)[CH2:34][CH2:33]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC(=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 4-[4-amino-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclo-hexanone (Intermediate AI) (0.90 g, 0.0022 mol), N-methylpiperazine (0.676 g, 0.0067 mol) and acetic acid (0.405 g, 0.0067 mol) in 1,2-dichloroethane (40 mL) was stirred for 10 min and sodium triacetoxyborohydride (0.62 g, 0.0029 mol) was added at once. The mixture was stirred at ambient temperature under an atmosphere of nitrogen for 24 hours and sodium triacetoxyborohydride (0.30 g, 0.0014 mol) was added. The mixture was stirred for another 48 hours, the solvent removed under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate solution (80 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer further extracted with dichloromethane twice (50 mL). The combined organic extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to yield a yellow oil. The compound was further purified by flash chromatography on silica gel using dichloromethane/triethylamine/methanol (89:10:1) as a mobile phase to yield cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AJ): TLC (dichloromethane/triethylamine=9:1) Rf 0.29 and trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine: TLC (dichloromethane/triethylamine=9:1) Rf 0.14.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:19][CH3:20]
Reactant: CCCI
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1C(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of methyl 2-hydroxybenzoate (1.05 g) and potassium carbonate (1.43 g) in dimethylformamide (10 ml) was added propyl iodide (1.41 g) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with 1N sodium hydroxide solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1) to give methyl 2-(propyloxy)benzoate as colorless oil (853 mg).
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([O:19]C)[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12]C)=[O:5].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5]
Reactant: COc1ccccc1C(=O)c1ccc(OC)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1O)c1ccc(O)c(Cl)c1Cl
Temperature: 200 °C

Procedure:
A solid mixture of 13 g of 2,3-dichloro-2',4-dimethoxybenzophenone and 52 g of pyridine HCl is heated at 200° C. for one hour. The hot mixture is then poured into vigorously stirred ice water. The product is extracted with ethyl acetate. The extract is dried over Na2SO4 and evaporated to give 2,3-dichloro-2',4-dihydroxybenzophenone, mp 197°-201° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][CH3:12])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].B.C1C[O:17]CC1.O>C1COCC1>[CH2:11]([C:3]([CH2:1][CH3:2])([CH2:8][CH2:9][CH2:10][OH:17])[C:4]([O:6][CH3:7])=[O:5])[CH3:12]
Reactant: C=CCC(CC)(CC)C(=O)OC
Reactant: C1CCOC1
Agent: B
Solvent: O
Product: CCC(CC)(CCCO)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 267.4 %

Procedure:
To a stirred solution of methyl 2,2-diethyl-4-pentenoate (Canney D J, Holland K D, Levine J A, McKeon A C, Ferrendelli J A, Covey D F (1991), supra.)(5.10 g, 30 mmol) in dry THF (10 mL), was added BH3.THF (1M, 12 mL, 12 mmol) slowly over a period of 15 min at 0° C. in a nitrogen atmosphere. After 2 h at 0° C., the reaction mixture was allowed to warm to room temperature (ca. 2 h). The reaction flask was immersed in an ice bath; water (5 mL) was added to destroy residual hydride, and the reaction mixture was oxidized by adding NaOH (3N, 3.2 mL) and then slowly adding 30% hydrogen peroxide (3.2 mL). After stirring for 1.5 h, the solution was poured into water (100 mL), and extracted with ether (3×50 mL). The combined ether extract was washed with 50 mL portions of water and brine, dried over MgSO4, and the solvent removed in vacuo to give 6.04 g of colorless oil. Column chromatography over silica gel (gradient elution, hexanes-EtOAc, 4:1 to 1:1) afforded the pure hydroxyester (2.79 g, 50%) as a colorless liquid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].II.CN([CH:15]=[O:16])C>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][CH:15]=[O:16]
Reactant: CN(C)C=O
Reactant: BrCCC1OCCO1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=CCCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To the solution of 2-(2-bromoethyl)-1,3-dioxolane (10 g, 55.2 mmol) in THF (50 mL) was added magnesium (1.6 g, 66.3 mmol) and trace amount of I2 as initiator. The reaction mixture was stirred at rt for 2 hrs. After cooling to −78° C., the mixture was quenched with dry DMF (1.39 g, 66.3 mmol) and kept at −78° C. for 2 hrs. After dilution with H2O the reaction mixture was extracted with CH2Cl2 (2×), followed by distillation (45-55° C. @ 8 mmHg) to afford 2 g (28%) of the title compound. MS (DCI/NH4+) m/z 131 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:24]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([CH2:30][CH2:31][NH:32][C:9](=[O:11])[CH2:8][CH2:7][CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[O:6]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)CCC1CCC(=O)O1
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(CCC1CCC(=O)O1)NCCc1ccccc1
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A solution of 2,3,4,5-tetrahydro-5-oxo-2-furanpropanoic acid (7.9 g) and N,N-carbonyldiimidazole (8.1 g) in dry dichloromethane (100 ml) was stirred under nitrogen at 20° for 30 minutes and a solution of 2-phenylethylamine (6.05 g) in dry dichloromethane (20 ml) was then added. The mixture was stirred at 20° for 2 hours. The solution was washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, water, dried (MgSO4), filtered and evaporated to give an oil which solidified on standing. Crystallisation from toluene gave the amide as fluffy crystals (10.4 g), mp 86°-87°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Sc1ccc(Cl)cc1
Product: COc1ccc2c(Sc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 4-chloro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 397 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[C:11]([C:14]([O:16]CC)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:24]([CH:27]=1)[C:25]#[N:26]>N1C=CC=CC=1>[C:25]([C:24]1[CH:27]=[C:20]([NH:19][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[OH:13])=[O:16])[CH:21]=[CH:22][C:23]=1[O:28][CH2:29][CH:30]([CH3:31])[CH3:32])#[N:26]
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1O
Reactant: CC(C)COc1ccc(N)cc1C#N
Solvent: c1ccncc1
Product: CC(C)COc1ccc(NC(=O)c2cnn(-c3ccc(F)cc3)c2O)cc1C#N
Temperature: 120 °C
Reaction time: 4 h
Yield: 12.7 %

Procedure:
Ethyl 1-(4-fluorophenyl)-5-hydroxypyrazole-4-carboxylate (1 g) and 5-amino-2-isobutoxybenzonitrile (0.8 g) were added to pyridine (10 ml) and the mixture was stirred at 120° C. for 4 h. After evaporation of the solvent under reduced pressure, hydrochloric acid was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethanol-diisopropyl ether to give the title compound (0.2 g), melting point: 207–208° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.I[CH2:45][C:46]([NH2:48])=[O:47]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:45][C:46]([NH2:48])=[O:47])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: NC(=O)CI
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NCC(N)=O)CC1

Procedure:
In a manner similar to the method described in example 160, (4-Amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with iodoacetamide (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2926.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH:10]12[CH2:11][CH2:12][CH:13]([CH:8]=[CH:9]1)[CH:2]1[C:1]([O:6][C:4](=[O:5])[CH:3]21)=[O:7]
Reactant: C1=CCCC=C1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2C3C=CC(CC3)C12
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of maleic anhydride (10.30 g, 105.0 mmol) in toluene (100 mL) was added 1,3-cyclohexadiene (8.41 g, 105.0 mmol). The mixture was heated to reflux temperature and allowed to react for 3 hrs. After cooling to room temperature, the solvent was evaporated and the remaining solid was recrystallized from EtOAc/hexane to yield pure bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride as colorless crystals: 14.11 g (75% yield), mp=117° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h

Procedure:
1.7 g (10.2 mmol) of ethyl 4-hydroxybenzoate, 1.76 g (9.3 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine and 2.44 g (9.3 mmol) of triphenylphosphine were dissolved in 40 ml of tetrahydrofuran. 1.62 g (9.3 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred overnight. The crude product was obtained by the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([S:24](Cl)(=[O:26])=[O:25])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:26])=[O:25])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(C(=O)O)c(Cl)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-chloro-5-chlorosulfonyl-4-fluorobenzoic acid as described in the synthetic METHOD B to give a white solid (26.5 mg) with purity >90%. MS (pos) m/z 421.4, 423.4.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13](Cl)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Cl)nc2ccn(Cc3ccccc3)c12
Reactant: N#Cc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(Cc3ccccc3)c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
In a sealed tube was added 5-benzyl-2-chloro-4-(2,6-dimethyl-4-nitrophenoxy)-5H-pyrrolo[3,2-d]pyrimidine (598 mg, 1.46 mmol), 4-aminobenzonitrile (691 mg, 5.85 mmol), TFE (9.1 mL) and TFA (1.97 mL, 11.7 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product (442 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13](O)=[O:14])=[N:9]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]([Cl:20])=[O:14])=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nnc(C(=O)Cl)n2)cc1
Temperature: 80 °C

Procedure:
Next, to a mixture of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid in Toluene (15 ml) at room temperature is added SOCl2 (1 ml, 13.70 mmol) and the mixture is heated at 80° C. for 3 hr. The reaction mixture is concentrated under reduced pressure to give the crude product, which is used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:5]=1[NH2:6].[C:15](Cl)(Cl)=[O:16]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:4]([O:3][CH3:2])[C:5]=1[N:6]=[C:15]=[O:16]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(N=C=O)c(OC)c1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
A suspension of 2,4,6-trimethoxyaniline hydrochloride (71.1 g, 0.324 mol) in a 12.5% wt/wt solution (540 mL) of phosgene in toluene was heated (95° C.) for 3 hours. Additional phosgene solution (2×270 mL) was added every hour. The mixture was allowed to cool and stirred under house vacuum for 2 days. The mixture was rotoevaporated to a solid. The solid was triturated with ether (450 mL), filtered, and the filtrate rotoevaporated to give a purple amorphous solid; yield 66.9 g (99%); mp 67°-70° C.
Reaction SMILES: [NH:1]([C:8]1[O:9][CH2:10][C:11](=O)[C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:2]1([NH:1][C:8]([C:12]2[C:13](=[O:15])[O:14][CH2:10][C:11]=2[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=C(Nc2ccccc2)OCC1=O
Reactant: Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1=C(Nc2ccccc2)COC1=O

Procedure:
The title derivative was obtained by a procedure similar to that described in Example 8 starting with 2-anilino-4-oxo-3-furoic acid (7.01 grams, 0.032 mol), triethylamine (8.98 ml, 0.064 mol), BOP-Cl (8.15 grams, 0.032 mol) and aniline (2.95 ml, 0.32 mol) dissolved in 100 ml methylene chloride. Yield: 7.37 g, mp 175°-176° C.
Reaction SMILES: [OH-].[Na+].C[C@:4]1([C:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1COCC1.CO>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:4]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 64 %

Procedure:
1N NaOH (1.2 ml, 1.2 mmol, 1.2 eq) was added to a stirred solution of (R)-1-tert-butyl 2-methylpyrrolidine-1,2-dicarboxylate (0.267 g, 1.0 mmol, 1 eq) in 4 ml of 3:1 THF/MeOH. After stirring overnight the solvent was removed in vacuo. The residue was dissolved in saturated aqueous NaHCO3 and extracted with Et2O (×2). The aqueous layer was adjusted to pH {tilde over ( )} 4 with 1N HCl and extracted with EtOAc (×4). The combined EtOAc fractions were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo yielding 0.1615 g (0.64 mmol, 64% yield) of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [C:1]1([S:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C1CCCCC1>[C:1]1([S:7][CH:8]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=CSc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: C1CCCCC1
Product: CCOC(=O)C1C(Sc2ccccc2)C1(C)C
Reaction time: 7 h

Procedure:
To a mixture of 1.94 g (11.8 mmol) of 2-methyl-1-propenyl phenyl sulfide, 200 mg anhydrous cupric sulfate and 10 ml cyclohexane heated under reflux is added, dropwise and with stirring over a 7 hr period, a solution of 6.58 g (58 mmol) of ethyl diazoacetate in 40 ml cyclohexane. After addition is complete, refluxing and stirring is continued for an additional 2 hr, and then the reaction mixture is filtered, dried and solvent is removed in vacuo to give ethyl 3-phenylthio-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]=[CH2:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][CH3:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Product: CCc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Yield: 98.6 %

Procedure:
25.0 g (0.0899 mol) of tert-butyl-dimethyl-(2-vinyl-5-methoxy-benzyloxy)-silane (15) was dissolved in 100 mL of ethyl acetate and was placed in a 1 L Parr Shaker bottle. 1.93 g (0.0084 mol) of catalyst (PtO2) was added and the solution was placed under 30 PSI of hydrogen for 25 minutes. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to yield crude product. The crude product was chromatographed on a silica gel column with 40% CHCl3 in hexane to afford 24.85 g (99%) of tert-butyl-dimethyl-(2-ethyl-5-methoxy-benzyloxy)-silane (16).
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:18])([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:17])([CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: CC1(C)CNCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)C2(C#N)CC2)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of (+/−)-6-bromo-4-((4,4-dimethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (50 mg, 0.104 mmol) in DMF (0.3 mL), was added 1-cyanocyclopropanecarboxylic acid (13.9 mg, 0.13 mmol), BOP (55.4 mg, 0.13 mmol), DIPEA (0.046 mL, 0.26 mmol). The mixture was stirred at rt for 3 h, quenched with water then filtered. The solid was rinsed with water, dried under vacuum to give 6-bromo-4-((1-(1-cyanocyclopropanecarbonyl)-4,4-dimethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (36 mg, 78% yield) was obtained as a brown solid. MS (ES+) m/z: 444.1, 445.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH:13][C:14]([CH3:41])([CH3:40])[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:22][CH:23]=2)[CH:18]=[N:17]1>>[Cl:8][C:7]1[C:2]([N:26]([CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH2:15][C:14]([OH:13])([CH3:40])[CH3:41])[N:17]=[CH:18]3)[S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)(=[O:29])=[O:28])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC(C)(C)O)c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3CC(C)(C)O)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-3 of Example 22).