Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16](Br)=[C:15]([Br:18])[N:14]=[C:13]2[CH:19]2[O:23][CH2:22][CH2:21][O:20]2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[O:24]1CCC[CH2:25]1.C([Mg]Br)C.Cl>CCOCC.C(OCC)(=O)C.CN(C)C=O>[Br:18][C:15]1[N:14]=[C:13]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:12]([CH2:11][C:3]2[C:2]([Cl:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[C:16]=1[CH:25]=[O:24]
Reactant: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1c(Br)nc(C2OCCO2)n1Cc1cc2c(cc1Cl)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of the product obtained in Stage A above is introduced into 200 ml of tetrahydrofuran and 10 ml of ethyl magnesium bromide in a 3M solution in ether is added dropwise. The reaction medium is maintained under agitation for 20 minutes at ambient temperature. 10 ml of dimethylformamide is then added to the reaction medium obtained and agitation is carried out for 2 hours at ambient temperature. The medium is hydrolyzed by the addition of 200 ml of dilute hydrochloric acid, extraction is carried out with ethyl acetate, followed by washing with water then drying and after impasting in isopropyl ether, 7.6 g of expected product is recovered, which is used as it is for the following stage.
Reaction SMILES: [N:1]([C:4]1[C:9](Cl)=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3].N(C1C([Br:32])=CN=CC=1C=O)=[N+]=[N-].NC1C(Cl)=CC(C#N)=CC=1Cl>>[N:1]([C:4]1[C:9]([Br:32])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(Br)cncc1C=O
Reactant: N#Cc1cc(Cl)c(/N=C/c2cncc(Cl)c2N=[N+]=[N-])c(Cl)c1
Agent: N#Cc1cc(Cl)c(N)c(Cl)c1
Product: N#Cc1cc(Cl)c(/N=C/c2cncc(Br)c2N=[N+]=[N-])c(Cl)c1

Procedure:
Following the procedure described for 4-{[1-(4-azido-5-chloropyridin-3-yl)meth-(E)-ylidene]amino}-3,5-dichlorobenzonitrile, 4-azido-5-bromo-pyridine-3-carbaldehyde and 4-amino-3,5-dichlorobenzonitrile were reacted to afford the title compound as a beige solid (quant. yield) that was used without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([NH2:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(=O)c2ccccc2O1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CC(N)c2ccccc2O1

Procedure:
A solution of 2′-hydroxyacetophenone (5.0 mL), acetone (4.7 mL), and pyrrolidine (5.4 mL) in 150 mL of methanol was stirred for 66 hours. The mixture was concentrated and treated with aqueous HCl (pH<1). The acidic layer was extracted twice with ethyl ether, which was dried and concentrated to provide 2,2-dimethylchroman-4-one. The 2,2-dimethylchroman-4-one was dissolved in 300 mL of methanol and treated with ammonium acetate (65 g) and sodium cyanoborohydride (2.5 g) for 24 hours. The resulting mixture was concentrated to 100 mL and diluted with 300 mL water. Concentrated HCl was carefully added until the pH was less than 1 and the acidic mixture was extracted with ethyl ether. The acidic phase was made basic with KOH and then extracted twice with ethyl ether. The basic extracts were dried and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:14])=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31]C1C=CC(C=O)=CN=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:31])=[CH:14][CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: Cc1ccc(C=O)cn1
Product: Cc1ccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 6-methylnicotinaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 8.38 (d, J=2.1 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J=2.07 Hz, 1H), 7.75 (d, J=2.07 Hz, 1H), 4.94-4.83 (m, 1H), 4.09-4.05 (m, 2H), 3.78-3.57 (m, 4H), 3.31-3.28 (m, 1H), 3.11-3.06 (m, 1H), 3.01-2.91 (m, 2H), 2.72-2.65 (m, 1H), 2.50 (s, 3H), 2.33-2.23 (m, 3H), 1.90-1.86 (m, 2H), 1.14 (d, J=7.1 Hz, 3H). MS: (M+H m/z 409.2).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[C:10]([C@@H:14]([CH3:18])[C:15]([OH:17])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7].O1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:51][O:52][C:53](=[O:57])[CH:54]([CH3:56])[NH2:55]>CN(C=O)C.CCCCCC.C(N(CC)CC)C>[CH3:51][O:52][C:53](=[O:57])[CH:54]([NH:55][C:15](=[O:17])[C@@H:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:9]=1)[CH3:18])[CH3:56]
Reactant: COC(=O)C(C)N
Reactant: C[C@@H](C(=O)O)c1cccc(C(=O)c2ccco2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)C(C)NC(=O)[C@H](C)c1cccc(C(=O)c2ccco2)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a solution of (R)-2-[3-(2-furanoyl)phenyl]propionic acid (V) (2 g, 8.2 mmol) in dioxane (5 mL) thionyl chloride (0.92 mL, 12.3 mmol) was added and the resulting solution was heated at reflux for 3 h. After cooling at room temperature the solvent was evaporated and the crude acyl chloride was dissolved in DMF (5 mL) at 0° C. and DCC (1.69 g, 8.2 mmol) and HOBT (1.01 g, 7.5 mmol) were added under stirring. After 30 min. a solution of D,L-alanine methyl ester hydrochloride (1.08 g, 7.5 mmol) and triethylamine (1.01 mL) in DMF (2 mL) was added. The resulting mixture was left stirring for 2 h at 0° C. and overnight at room temperature. The precipitated DCU was filtered off; the filtrate was diluted with EtOAc (15 mL) and the organic phase washed with 10% citric acid buffer (2×10 mL), with a saturated solution of NaHCO3 (2×10 mL) and then with brine (10 mL). After drying over Na2SO4, solvent was evaporated to give a crude that was suspended in n-hexane (20 mL) and left stirring overnight at room temperature. 2-[(R)-2-[3-(furan-2-carbonyl)phenyl]propionylamino]propionic acid methyl ester was isolated by filtration as white powder (1.66 g, 5.7 mmol). Yield 69%. To a solution of the methyl ester in dioxane (3 mL), 1N NaOH (5.7 mL) was added and the mixture left stirring overnight at room temperature. An ice/water mixture (40 mL) was added and the resulting mixture was acidified with conc. H2SO4 to pH=2. The aqueous phase was extracted with CH2Cl2 (4×15 mL) and the collected organic extracts were washed back with brine (15 mL), dried over Na2SO4 and evaporated under vacuum to give an oily residue. 37 was isolated by crystallization from ethyl ether (10 mL) as white solid (0.72 g, 2.28 mmol). Yield 40%.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([C:16]#[N:17])[C:5](=[O:15])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:18][C:3]1[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:5](=[O:15])[C:4]=1[C:16]#[N:17]
Reactant: Cc1ccccc1-n1cc(Br)c(Cl)c(C#N)c1=O
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-n1cc(-c2ccccc2)c(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 64.3 %

Procedure:
A mixture of 5-bromo-4-chloro-1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (400 mg), phenylboronic acid (211 mg), tetrakis(triphenylphosphine)palladium(0) (143 mg), aqueous sodium carbonate solution (2 M, 1.24 mL) and 1,2-dimethoxyethane (4.0 mL) was heated with microwave irradiation at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (255 mg).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([CH3:20])=[N:9][N:10]([CH3:19])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]>CO>[CH2:12]([C:11]1[N:10]([CH3:19])[N:9]=[C:8]([CH3:20])[C:7]=1[C:5]([OH:6])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(C)nn(C)c1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(C)c(Cc2ccccc2)c1C(=O)O
Temperature: 50 °C

Procedure:
NaOH (10 N, 7 mL) is added to a solution of 5-benzyl-1,3-dimethyl-1H-pyrazole-4-carboxylic acid methyl ester (680 mg, 2.78 mmol) in MeOH (10 mL) at RT. The mixture is heated to 50° C. for 4 h. The solvent is removed to dryness. H2O is added and pH is adjusted to 5 using aq. HCl. The solid is filtered and dried to give the title compound.
Reaction SMILES: C(OCO[C@H:6]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:8]([C:9](=[O:35])[CH2:10][C@@H:11]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:12]3[CH2:13][C@@H:14]3[O:19][C@@:18]4([O:25][CH2:24][C@H:22]([CH3:23])[CH2:21][CH2:20]4)[C@@H:16]([CH3:17])[C@@H:15]32)[CH2:7]1)C.[OH-].[Na+]>Cl.CO.O1CCCC1>[CH3:17][C@@H:16]1[C@:18]2([O:25][CH2:24][CH:22]([CH3:23])[CH2:21][CH2:20]2)[O:19][C@H:14]2[CH2:13][C@@H:12]3[C@@:26]([CH3:34])([C@@H:15]12)[CH2:27][CH2:28][C@H:29]1[C@H:11]3[CH2:10][C:9](=[O:35])[CH:8]2[C@:30]1([CH3:33])[CH2:31][CH2:32][CH2:6][CH2:7]2
Reactant: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC(=O)C5CCCC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 62 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Concentrated hydrochloric acid (2 drops) was added to a solution of (3β,5α,25R)-3-ethoxymethoxy-spirostan-6-one (0.70 g, 1.43 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). The mixture was stirred under nitrogen atmosphere and heated to 62° C. After 15 minutes, the reaction was cooled to 0° C. and neutralized with 15% sodium hydroxide solution. The mixture was concentrated in vacuo then diluted with ethyl acetate. The organic layer was washed with water (2×), brine (1×), dried (sodium sulfate), concentrated in vacuo and purified by flash chromatography (1:1 hexane/ethyl acetate) to afford 0.55 g (89.4%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:26]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC1=CCCCCCCCCCC1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCCCCCCC1
Yield: 78.9 %

Procedure:
The compound 8 (375 mg, 1 mmol) was converted to the enol ether with 1-methoxycyclododecene (589 mg, 3 mmol) in the same manner as the example 10 to give the compound 13 (426 mg, 79 %) as oil. Rf 0.57 (Al2O3 60, Type E, 10:1 toluene - EtOAc).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([Br:12])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2c(N)cccc2o1
Solvent: CN(C)C=O
Product: Cc1nc2c(N)ccc(Br)c2o1
Temperature: -5 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
Compound 474B (3.90 g, 26.3 mmol) was dissolved in DMF (45 mL) and cooled to −5° C. and N-bromosuccinimide (4.68 g, 26.3 mmol) was added in small portions and the reaction stirred for 5 h. The mixture was poured into 150 mL of ice water to give a cream colored solid which was filtered, washed with water, dissolved in CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel eluting with 20% ether/CH2Cl2 gave compound 474C (3.36 g, 56%) as a beige solid. HPLC: 95.4% at 2.583 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 228.03 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light grey solid (73 mg, 88%), MS (ISP) m/z=332.5 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:10]([OH:17])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:19]([C:29]([F:30])([F:31])[F:32])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:17][C@H:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:9]2)=[O:25])[C:22]1([CH3:28])[CH3:27]
Reactant: O[C@@H]1C[C@@H](Cc2ccccc2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2ccccc2)c2ccccc21
Yield: 61.9 %

Procedure:
In the manner of Example 4, the reaction of 0.6 g (0.0027 mole) of trans-3-phenylmethyl-1-indanol (96% trans, 4% cis) and 0.704 g (0.0027 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (which may be prepared by method disclosed in U.S. Pat. No. 4,238,505, Example 7) in the presence of 0.214 g (0.0027 mole) of pyridine and 50 mL of toluene gave 0.75 g of trans-3-phenylmethyl-1-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1)(=[O:14])=[O:13])(C)(C)C.CO>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[NH2:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1)(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Reaction time: 4 h
Yield: 100 %

Procedure:
A 4N HCl solution in 1,4-dioxane (22 mL) is added to a stirred solution of [2-(7-phenyl-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (2.50 g, 5.85 mmol) in CH2Cl2 (40 mL)/CH3OH (6 mL) at ambient temperature under nitrogen. The resultant white suspension is stirred for 4 hours. At filtration and vacuum drying at 50° C., 2.34 g (5.85 mmol, 100% yield) of the title compound is obtained as a white solid. ESIMS: m/z 328 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]2[C:10](=[O:15])[O:11][C:12](=O)[NH:13][C:8]=2[CH:7]=[C:6]([Cl:16])[CH:5]=1>CO>[NH2:13][C:8]1[CH:7]=[C:6]([Cl:16])[CH:5]=[C:4]([Cl:3])[C:9]=1[C:10]([O:11][CH3:12])=[O:15]
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(N)cc(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a stirred solution of sodium hydroxide (0.070 g, 1.8 mM) in methanol (8.5 mL) was added 5,7-dichloro-2H-3,1-benzoxazine -2,4(1H)-dione (4.13 g, 17.8 mM). The reaction mixture was stirred at 55° C. for 2 hr, allowed to cool to room temperature and concentrated. The residue was diluted with water and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave the methyl 2-amino-4,6-dichlorobenzoate (3.61 g, 92.1%) as a brown solid; MS(CI): 220 (M+H).
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:32])[NH:9][CH:10]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20]4[N:21]=[N:22][NH:23][N:24]=4)[CH:17]=3)[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33]N(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].IC>CC#N.O.C1COCC1>[CH:1]1([O:7][C:8](=[O:32])[NH:9][CH:10]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20]4[N:21]=[N:22][N:23]([CH3:33])[N:24]=4)[CH:17]=3)[N:12]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(NC1Cc2cc(-c3nn[nH]n3)ccc2N(Cc2ccccc2)C1)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc3c(c2)CC(NC(=O)OC2CCCCC2)CN3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of [1-benzyl-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydroquinolin-3-yl]-carbamic acid cyclohexyl ester (61 mg, 0.14 mmol), prepared as described in Example 53, in CH3CN (0.5 mL)-DMF (0.5 mL)-THF (0.5 mL) at RT was added Cs2CO3 (63.4 mg, 0.19 mmol), followed by iodomethane (7.8 μL, 0.126 mmol). The reaction mixture was stirred at RT for 16 h and then diluted with H2O, extracted with EtOAc (10 mL×3). The organic extracts were washed saturated aqueous NaCl, dried Na2SO4), and concentrated. The resulting residue was purified using preparative HPLC [YMC S5 ODS (20×100 mm); Eluted with 50% to 90% B, 8 min gradient and 7 min hold. (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH); Flow rate at 20 mL/min. UV detection at 220 nm] to give the title compound (regioisomer A, 35 mg, 56%) as a white solid. HPLC (method B): 98% pure, retention time=7.9 min. MS (ES): m/z 447 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][CH:17]=1.O>CN(C=O)C>[N:16]1([C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(Cl)nc(-n2cnc3ccccc32)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
30.5 g (167 mmol) of 2,4,6-trichloropyrimidine dissolved in DMF (300 ml) was cooled to −5° C., added with potassium carbonate (40 g) and benzimidazole (17.7 g, 150 mmol) and stirred for 30 minutes. The reaction mixture was further stirred at room temperature overnight. The reaction mixture was added with water (500 ml) and the precipitated crystals were collection by filtration. The obtained crude crystals were purified by silica gel chromatography to obtain 12.8 g (yield: 32%) of 2-(benzimidazol-1-yl)-4,6-dichloropyrimidine with melting point of 173° C. -175° C. as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH:29][CH3:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][O:16][CH:11]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:3]=[C:2]2[N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30]
Reactant: C[Si](C)(C)CCOCn1nc(Cl)c2cc(C3OCCCO3)ccc21
Reactant: CNCCOC
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCN(C)c1nn(COCC[Si](C)(C)C)c2ccc(C3OCCCO3)cc12
Temperature: 25 °C
Yield: 54 %

Procedure:
To a degassed solution of 400 mg (1.08 mmol) 3-chloro-5-(1,3-dioxan-2-yl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-indazole (Example 45A) and 135 mg (1.52 mmol) 2-methoxy-N-methylethanamine in anhydrous THF (11 ml) were added under inert gas atmosphere 103 mg (0.22 mmol) 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (XPhos), 50 mg (0.054 mmol) tris(di-benzylideneacetone)dipalladium(0) (Pd2dba3) and 5.42 ml (5.42 mmol) lithium hexamethyldisilazide solution (1 M in THF). The resulting mixture was stirred under reflux for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was washed with water and with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 90:10 v/v) to yield the title compound as a white solid (246 mg, 42% of th.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[Cl:20]N1C(=O)CCC1=O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][C:15]=1[Cl:20]
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCBr
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1ncc(Cl)c1-c1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A mixture of 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole (470 mg, 1.44 mmole), and N-chlorosuccinimide (1.44 mmole, 1.0 eq) in 2 mL of DMF was stirred at 100° C. for 20 minutes in the Microwave. The mixture was quenched with water, extract with ethyl acetate, and dried in vacuo give the title compound as a yellow solid (462 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 3.61 (t, 2H), 3.78 (s, 3H), 4.44 (t, 2H), 7.13 (d, 1H), 7.57 (s, 1H), 8.23 (s, 1H), 8.40 (d, 1H). Exact mass calculated for C12H1181BrClN3O3 359.0. found 362.0 (MH+).