Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:16][C:17]#[N:18])[C:4]2[C:9]([C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2.[CH2:19]([OH:21])[CH3:20]>C(Cl)(Cl)Cl>[ClH:1].[CH2:19]([O:21][C:17](=[NH:18])[CH2:16][N:3]1[C:4]2[C:9](=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2)[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:2]1[Cl:1])[CH3:20]
Reactant: CS(=O)(=O)c1c(Cl)n(CC#N)c2ccc(Cl)cc12
Reactant: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=N)Cn1c(Cl)c(S(C)(=O)=O)c2cc(Cl)ccc21
Product: Cl
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of (2,5-dichloro-3-methylsulfonyl-indol-1-yl)-acetonitrile (0.303 g, 1 mmole) in dry chloroform (15 ml) was cooled to 0° C. under a nitrogen atmosphere. To this solution was added anhydrous ethanol (0.35 ml). Dry hydrogen chloride gas was bubbled into the reaction mixture to saturation at 0° C. The flask was stoppered and stirred for 2 h at 0 and left in the freezer overnight. The resulting white solid precipitate was filtered off and dried to afford 0.353 g (91%) of 2-(2,5-dichloro-3-methanesulfonyl-indol-1-yl)-acetimidic acid ethyl ester hydrochloride.
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C([O-])(=O)C.[NH4+:33].N>CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH:3]=[C:4]([NH2:33])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CO
Product: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 55 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
A mixture of 7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (22.1 g), ammonium acetate (25 g), methanol (220 mL), and aqueous ammonia (22 mL) are heated to about 55° C. and stirred for about 6 hours. The reaction mass is then cooled to 30° C. and the undissolved particles are filtered off. The filterate is distilled off completely under vacuum. To the residue, ethanol (25 mL) is charged and the mixture is stirred at about 30° C. for about 30 minutes. The solid is filtered, washed with ethanol (5 mL), and dried to afford the title compound. (Yield: 75%; purity by HPLC: 96.7%)
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:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[CH3:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([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:23])=[O:22])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C)c(Cl)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3-chloro-4-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.7 mg) with purity >90%. LCMS (pos) m/z 375.2.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:14])([F:13])[C:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[NH2:15][C:16]1[S:17][C:18]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:20]=1.O>CN(C)C(=O)C>[C:23]1([C:21]([C:18]2[S:17][C:16]([NH:15][C:8](=[O:9])[C:7]([OH:12])([CH3:11])[C:6]([F:14])([F:13])[F:5])=[CH:20][CH:19]=2)=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)s1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)s1)C(F)(F)F
Reaction time: 1 h

Procedure:
Thionyl chloride (110 μl, 1.51 mmol) is added to 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (240 mg, 1.52 mmol) in 5 ml of N,N-dimethylacetamide at -15°/-10° C., and the mixture is stirred at this temperature for one hour. Then 2-amino-5-(phenylcarbonyl) thiophene (200 mg, 0.983 mmol) is added and the reaction mixture is equilibrated to room temperature. After the reaction has ended, the reaction mixture is poured into 200 ml of water and subjected to extraction with 3×100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The orange-colored oil which remains is purified by flash chromatography (eluent: 50% v/v ethyl acetate in petroleum ether (40/60)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.Cl[C:32]([O:34][CH3:35])=[O:33].O>C(Cl)Cl>[CH3:35][O:34][C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:33]
Reactant: COC(=O)Cl
Reactant: CN(CCN(CCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCCN(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
To a solution of tert-butyl 2-((3-aminopropyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (300 mg, 0.88 mmol) in dry CH2Cl2 (5 mL), Et3N (583 mg, 5.3 mmol) was added. The resulting mixture was cooled to 0-5° C. and a solution of methyl chloroformate (965 mg, 10.3 mmol, 5 eq) in dry CH2Cl2 (5 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Upon completion of the reaction, water (10 mL) was added, the aqueous layer was extracted with CH2Cl2 (3×8 mL), the combined organic layers were washed with 10% citric acid (2×5 mL) and brine, then dried over Na2SO4. The filtrate was concentrated to the crude product which was purified by preparative HPLC to tert-butyl 2-((3-(methoxycarbonylamino)propyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (200 mg, yield 83%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=[CH2:17].[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]O>CN(C1C=CN=CC=1)C>[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH3:27])=[O:23])=[CH:20][CH:19]=1)=[CH2:17]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: COCCOCCOCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C=Cc1ccc(C(=O)OCCOCCOCCOC)cc1
Yield: 78 %

Procedure:
As described in Example 6a) the compound was obtained by reacting together DCC (3.1 g, 14.9 mmol), 4-vinylbenzoic acid (2.0 g, 13.5 mmol), DMAP (1.3 g, 10.8 mmol) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol (3.3 g, 20.3 mmol) for 2 days. Flash-chromatography over SiO2 (heptane/ether gradient) and drying under high vacuum gave 3.1 g of a slightly yellow oil (yield: 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]#[C:16][C:17](=O)[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[NH:28][N:27]=[C:17]([CH3:18])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)C#CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 4-[1-phenyl-1-(3-oxo-1-butyn-1-yl)methylene]-piperidine-1-carboxylic acid tert-butyl ester(0.365 g, 1.069 mmol) and hydrazine hydrate (0.065 mL, 1.14 mmol) in EtOH (5 mL) was allowed to stir at rt for 2 h and then it was heated at 80° C. for 14 h. The solvent was subsequently removed under reduced pressure and the residue was purified by preparative HPLC affording the title compound (0.151 g, 40%) as a colorless solid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C2C=CC=CC=2)=[C:4]([F:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[N:20]([O-])=O.[Na+].[ClH:24]>O>[ClH:24].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:20])=[C:4]([F:15])[C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=N[O-]
Reactant: Fc1c(Nc2ccccc2)ccc(Br)c1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)c(C(F)(F)F)c1F
Reaction time: 0.5 h

Procedure:
A sample of 4-bromo-2-fluoro-3-trifluoromethyl-phenyl aniline (4 g, 15.5 mmol) is suspended in concentrated HCl (36 mL) and cooled in an ice/salt bath. The reaction is then treated dropwise with a solution of NaNO2 (1.12 g, 16.3 mmol) in water (36 mL). The reaction is allowed to stir for 30 minutes and then treated with a solution of SnCl2 dihydrate (17.5 g, 77.5 mmol) in concentrated HCl (36 mL). The reaction is then stirred for 1 hour in an ice/water bath followed by an hour at room temperature. The reaction is then filtered and the solid is treated with aqueous 50% NaOH solution (30 mL) and ether (50 mL). The aqueous phase is extracted once more with ether and the combined organics are dried over MgSO4 and filtered. The resulting solution is treated with 5 mL of 4 M HCl in dioxane while stirring and the resulting solid is collected and dried under high vacuum to afford 2.44 g of (4-Bromo-2-fluoro-3-trifluoromethyl-phenyl)-hydrazine hydrochloride; LC/MS calculated for [M+H]+ C7H5BrF4N2: 273.0, found: 272.9.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.ClC(OCC)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>CC(C)=O.O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:34]=[N+:35]=[N-:36])=[O:17])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(C(=O)O)cc2)nc1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCc1ccc(-c2ccc(C(=O)N=[N+]=[N-])cc2)nc1
Yield: 93.7 %

Procedure:
A solution of 2.1 g of p-(5-pentyl-2-pyridyl)benzoic acid in 80 ml of acetone was cooled to 2° C. while stirring and gassing with nitrogen and treated dropwise within 10 minutes with a solution of 2.16 ml of triethylamine in 15 ml of acetone. The reaction mixture was then treated dropwise at 1°-2° C. within 10 minutes with a solution of 1.86 ml of ethyl chloroformate in 8 ml of acetone and stirred at this temperature for a further 30 minutes. Subsequently, a solution of 1.38 g of sodium azide in 8 ml of water was added dropwise to the reaction mixture at 1°-2° C. within 10 minutes and the resulting mixture was stirred for a further 1 hour in an ice-bath. Thereafter, the reaction mixture was poured into 200 ml of water and extracted with diethyl ether. The organic phase was washed with water, dried over sodium sulphate, filtered and freed from solvent. Purification of the resulting light yellowish crystals (2.1 g) by chromatography on 120 g of silica gel with 1 l of methylene chloride gave 2.15 g of p-(5-pentyl-2-pyridyl)benzoic acid azide as a light yellowish paste.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][O:16]1>>[O:1]=[C:2]1[C:10](=[CH:24][C:23]2[NH:22][CH:21]=[C:20]3[C:15](=[O:14])[O:16][CH2:17][CH2:18][C:19]=23)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-carboxylic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: NC(=O)c1cccc(Br)c1
Reactant: CC(C)(C)C=O
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cccc(Br)c1)n1nnc2ccccc21

Procedure:
A suspension of 3-bromobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(Cl)Cl.CO>[N:28]1[CH:33]=[C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:16]=[CH:17][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]6)=[CH:19][CH:20]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[N:30][CH:29]=1
Reactant: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: c1ncc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 29.7 %

Procedure:
A mixture of 6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (40 mg, 0.08 mmol), pyrimidin-5-yl boronic acid (20 mg, 0.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.2 mg, 0.004 mmol) in saturated aqueous sodium carbonate solution (0.15 mL) and acetonitrile (1.50 mL) was heated under microwave irradiation at 130° C. for 30 minutes. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative HPLC [0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min] to afford the title compound as a yellow/orange solid (10 mg, 23%). 1H NMR (DMSO-D6, 400 MHz): 12.44 (s, 1H), 9.52 (s, 2H), 9.21 (s, 1H), 9.08 (d, J=1.7 Hz, 2H), 9.02 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.53 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=6.84 min, M+H+=421.
Reaction SMILES: Cl.C([C:4]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)[N:5]=1)C.N1N[CH:21]=C2CCCC=12>>[N:6]1([CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([NH2:18])[CH2:16][CH2:17]2)[C:7]2[CH2:9][CH2:10][CH2:21][C:8]=2[CH:4]=[N:5]1
Reactant: CCc1cc(CC)n(C[C@H]2CC[C@H](N)CC2)n1
Reactant: c1[nH]nc2c1CCC2
Agent: Cl
Product: N[C@H]1CC[C@H](Cn2ncc3c2CCC3)CC1

Procedure:
This compound was prepared analogously to Intermediate B by replacing 3,5-diethyl-1H-pyrazole with 2,4,5,6-tetrahydrocyclopenta[c]pyrazole; LCMS Rt=1.39 min, [M+H]+ 234.29; Method LowpH_v002.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[CH:16]12[CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH:17]2[NH2:23].C(N(CC)C(C)C)(C)C.Cl>O.O1CCOCC1>[C@H:16]12[CH2:22][C@H:19]([CH2:20][CH2:21]1)[CH2:18][C@H:17]2[NH:23][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: NC1CC2CCC1C2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Reaction time: 19 h
Yield: 99.2 %

Procedure:
To a mixture of methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (4.0 g), rac-(1R,2R,4S)-bicyclo[2.2.1]heptan-2-amine (3.7 g), and 1,4-dioxane (60 mL) was added N,N-diisopropyl ethylamine (4.3 mL) at room temperature, and the mixture was stirred at the same temperature for 19 hours. To the reaction mixture were added water and 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain methyl rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (5.2 g) as a yellowish white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27]([CH:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)[CH:28]=1>CO.O>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]4)[CH:28]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)C1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)C1

Procedure:
A stirred solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.150 g, 0.446 mmol), 4-amino-1-(1-Boc-pyrrolidin-3-yl)-1H-pyrazole (0.225 g, 0.892 mmol) in MeOH (10 mL) and water (1.0 mL) was heated at 70° C. for 2 days. Additional 4-amino-1-(1-boc-pyrrolidin-3-yl)-1H-pyrazole (0.125 g, 0.446 mmol) was added and the mixture was heated for a further 16 hours at reflux. After cooling the solvent was removed to afford a crude red oil which was purified by silica gel column chromatography (0-100% EtOAc in cyclohexane) to give the title compound A21 as a red oil (0.164 g, 67% yield). LCMS-C: rt 5.51 min; m/z 551.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2C1CCCCO1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a flask (1 L) under N2 at room temperature, were added 3,6-dibromocarbazole (50 g), dichloromethane (500 mL), 3,4-dihydro-2H-pyran (40 g), p-toluenesulfonic acid monohydrate (1 g). The reaction was stirred overnight. NaHCO3 (3 g) was added, and the reaction was stirred for 1 h. After filtration, the solvent in the filtrate was removed by evaporation. MeOH (1 L) was added for reflux under N2 for 2 h. Filtration when it was warm gave 37.5 g product. The MeOH (800 mL) was removed by evaporation, and solid came out. Filtration gave 12.5 g product. Both products are white, single spot on TLC, and GS-MS and 1H NMR showed they are pure product. The overall yield is 80%. Second and Third Reactions following the reaction scheme above produce compound (2) and (3), respectively, according to the scheme below:
Reaction SMILES: [CH2:1]([N:8]1CC2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O-].[Na+].[C:17]([OH:20])(=O)[CH3:18]>CO>[CH2:1]([N:8]1[CH2:18][C@@H:17]([O:20][CH3:14])[C@H:10]([OH:11])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
34.9 g (0.2 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane (U.S. Pat. No. 4,254,135) are heated with 3.6 g (20 mmol) of sodium methylate solution (30% strength) at 120° C. in 200 ml of absolute methanol in an autoclave for 10 hours. After cooling, the mixture is neutralized with 1.2 g (20 mmol) of acetic acid and the solvent is removed on a rotary evaporator. The residue is taken up in tetrahydrofuran and the sodium acetate is filtered off. The filtrate is concentrated and the residue is distilled.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)([OH:3])=[O:2].[CH:19](O)([CH3:21])[CH3:20]>>[CH:19]([O:2][C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)=[O:3])([CH3:21])[CH3:20]
Reactant: CCc1cc(C(=O)O)c2cc(C(C)C)cccc1-2
Reactant: CC(C)O
Product: CCc1cc(C(=O)OC(C)C)c2cc(C(C)C)cccc1-2

Procedure:
The acid chloride derivative (12) was produced in the same manner as in the synthesis of the above-mentioned 1-ethoxycarbonyl-3-ethyl-7-isoproylazulene (13) using 1-carboxy-3-ethyl-7-isopropylazulene (11) (1.21 g) as a starting material. Isopropanol was employed in place of the ethanol under the same reaction conditions and treatment as above to obtain the product (14) in a dark purple crystalline form, at a yield of 1.34 g (94.2%), having a melting point of 69 to 71° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:18])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a solution of 3.00 g (0.011 mol) of the product of Example 13 in 30 mL of DMF was added 4.76 g (0.034 mol) of potassium carbonate followed by 1.43 mL (0.023 mol) of iodomethane. The reaction was stirred at room temperature for 5 h and then diluted with water and extracted with ether. The combined organics were washed water, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 3.0 g (95%) of the N-methyl sulfonamide as a colorless oil. Electrospray Mass Spec 275.9 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]([CH3:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].C(O)C.[NH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]([CH3:15])[C:3]([C:16](=[O:19])[CH2:17][CH3:18])=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([S:24]([NH2:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a solution of 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)propan-1-one (compound 49b, 3.0 g, 8.81 mmol) in a mixture of toluene:ethanol (15 ml:45 ml) were added 4-aminosulfonylbenzene boronic acid (1.947 g, 9.69 mmol) and potassium carbonate (2.43 g, 17.61 mmol) at 25° C. in a sealed tube and a nitrogen gas was bubbled through it for 15 minutes. To the reaction mixture was the added tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) under nitrogen atmosphere and reaction mixture was heated at about 90 to about 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane. The combined filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.22 g, 33.2%).