Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: CN(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C1CCN(c2ccc(N)cc2)CC1
Yield: 85.3 %

Procedure:
A solution of N,N-dimethyl-1-(4-nitrophenyl)piperidine-4-carboxamide (2.5 g, 9.01 mmol) and 0.3 g of Pd/C in 20 mL of MeOH, under H2, was stirred at room temperature for 5 hours. The mixture was filtered, and the volatiles were removed in vacuo to give 1.9 g of 1-(4-aminophenyl)-N,N-dimethylpiperidine-4-carboxamide.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:21]([CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C.COC(OC)OC>[C:21]([CH:25]1[CH2:26][CH2:27][CH:28]([NH:31][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:20])=[CH:13][CH:14]=2)[CH2:29][CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: O=Cc1ccc(C(=O)N(CCC(=O)O)CC2CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(NCc2ccc(C(=O)N(CCC(=O)O)CC3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above resin bound 3-[cyclopropylmethyl-(4-formylbenzoyl)amino]propionic acid (50 mg) was treated with 1 mL 0.5 M (0.5 mmol, 77.5 mg) 4-tert-butylcyclohexylamine solution in DMF:trimethylorthoformate 1:1, 100 μL glacial acetic acid and sodium cyanoborohydride (750 μmol, 48 mg) suspended in 0.5 mL DMF:trimethylorthoformate 1:1. Overnight shaking at 25° C. followed by filtration and washing with 2×1 mL 20% H2O in DMF, 3×1 mL DMF and 2×1 mL dichloromethane afforded the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].Cl>N1C=CC=CC=1>[C:13]([O:16][NH:12][C:6]1([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:15])[CH3:14]
Reactant: NC1(c2cccs2)CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)ONC1(c2cccs2)CCCCC1
Reaction time: 4 h

Procedure:
The amine of Stage 17c (3 g, 16.6 mmoles) in pyridine (100 ml) is introduced into a 250 ml three-necked flask, and acetic anhydride (51 g, 50 mmoles) is added dropwise. After 4 hours under agitation at ambient temperature, 100 ml of an HCl solution (10%) is added and the product formed is extracted with ether (3×50 ml). The organic phase is washed with an HCl solution (10%) (2×80 ml), then with water (2×80 ml), dried over MgSO4 and concentrated to dryness. In this way, a white solid is obtained (3.1 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][C:13]=1[CH3:14].O.NN>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccn(N2C(=O)c3ccccc3C2=O)c1-c1ccc(Cl)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccn(N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 2-[2-(2,4-dichlorophenyl)-3-methyl-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)-dione (3.71 g, 10.0 mmol) in EtOH (60.0 mL) is added hydrazine monohydrate (1.21 mL, 1.25 g, 25.0 mmol) at room temperature. The reaction mixture is heated at reflux for 2 h. After cooling down to room temperature, the mixture is filtered. The filtrate is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 2.36 g (98%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.1 Hz, 1H), 7.37 (dd, J=2.1, 8.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.5, 135.0, 134.6, 130.0, 129.9, 127.6, 127.3, 122.8, 117.0, 106.9, 12.3; IR (liq.) 2422, 2350, 2327, 2286, 2211, 1563, 1547, 1484, 1102, 1001, 868, 826, 806, 724, 708 cm-−1; MS (EI) m/z 243 (M++H), 241 (M++H); HRMS (FAB) calcd for C11H10Cl2N2+H 241.0299, found 241.0291.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=1)[C:19]([O:21][CH3:22])=[O:20]>C(O)C>[C:37]([O:36][C:34]([NH:33][C:30]1[CH:29]=[CH:28][C:27]([S:26][C:25]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[NH:15][C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Reactant: CC(C)c1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3cc(C(C)C)ccc23)c1
Yield: 33 %

Procedure:
The products of Example 431F (0.572 g, 2.768 mmol) and methyl 3-amino-4-(4-(tert-butoxycarbonylamino)phenylthio)benzoate the product of Example 385C or Example 432C (0.902 g, 2.409 mmol) were reacted in anhydrous ethanol (25 mL) under a nitrogen atmosphere at reflux for 30 minutes. The reaction was cooled and concentrated by rotary evaporation. The residue was dissolved in methylene chloride (50 mL) and washed with saturated aqueous sodium hydrogencarbonate (25 mL) and water (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with 3:97 methanol/methylene chloride afforded the title compound as a white solid (0.505 g, 0.927 mmol, 33%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.32 (d, J=6.99 Hz, 6 H) 1.48 (s, 9 H) 2.99-3.21 (m, 1 H) 3.83 (s, 3 H) 6.93 (d, J=8.46 Hz, 1 H) 7.37 (d, J=8.82 Hz, 2 H) 7.55 (d, J=8.82 Hz, 2 H) 7.55-7.64 (m, 2 H) 7.75 (dd, J=8.46, 1.84 Hz, 1 H) 7.91 (d, J=1.84 Hz, 1 H) 8.41 (d, J=8.46 Hz, 1 H) 8.45 (s, 1 H) 9.62 (s, 1 H) 9.92 (s, 1 H). MS (ESI+) m/z 545 (M+H)+.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@@H:20]4[CH2:24][C@@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>C(C#N)(C)=O>[S:34](=[O:36])(=[O:35])([O:26][CH2:25][C@@H:23]1[CH2:24][C@@H:20]([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[CH:21]=[CH:22]1)[NH2:37]
Reactant: NS(=O)(=O)Cl
Reactant: OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Agent: CC(=O)C#N
Solvent: c1ccncc1
Product: NS(=O)(=O)OC[C@H]1C=C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of ((1R,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopent-2-en-1-yl)methanol (35.7 mg, 0.103 mmol) and pyridine (0.0417 mL, 0.515 mmol) in AcCN (1.00 mL) at 0° C. under an atmosphere of nitrogen was added dropwise a 2.00 M solution of chlorosulfonamide in AcCN (0.260 mL, 0.520 mmol, as prepared in 1j). The solution was stirred for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate solution and partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to afford the title compound as a solid (28.9 mg, 66%). 1H NMR (400 MHz, CDCl3, δ): 8.36 (s, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.30-7.18 (m, 3H), 6.89 (d, J=3.6 Hz, 1H), 6.32 (d, J=3.5 Hz, 1H), 6.14-6.12 (m, 1H), 6.04-5.97 (m, 2H), 5.89 (br s, 1H), 4.19 (dd, J=1.2, 6.0 Hz, 2H), 3.43-3.37 (m, 1H), 3.09-3.01 (m, 1H), 2.98-2.90 (m, 1H), 2.77-2.69 (m, 1H), 2.46-2.39 (m, 1H), 2.07-1.93 (m, 3H) ppm. LC/MS: Rt=1.24 min, ES+ 426 (FA standard).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH:27]=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:3][CH2:2]1.I[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][N:43]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[NH:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:32][CH2:33][CH:34]([C:37]([OH:40])([CH3:38])[CH3:39])[CH2:35][CH2:36]4)[CH:27]=[CH:26][C:9]=3[N:10]=2)=[N:43]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1
Reactant: Ic1n[nH]c2ccccc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4n[nH]c5ccccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
To a degassed solution of 2-(1-((4-morpholino-2-(tributylstannyl)pyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 136 (0.15 g) and 3-iodo-1H-indazole (1.4 eq) in 1,4-dioxane (1.4 mL) was added Copper(I) thiophene-2-carboxylate (1 eq) and Tetrakis(triphenylphosphine)palladium(0) (0.125 eq). The reaction was microwaved at 140° C. for 30 minutes and then loaded onto biotage isolute scx-2 cartridge and eluted with 2M ammonia in Methanol. The crude material was purified by reverse phase HPLC to afford 23.4 mg of 138. MS (Q1) 488.3 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC(C)(C)C(NC)=O>>[CH3:12][C:7]([CH3:11])([C:8]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:9])[CH2:6][O:5][C:4]1[C:3]([O:2][CH3:1])=[C:16]([O:17][CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][C:23]2=[O:28]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: C1COCCN1
Agent: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)N2CCOCC2)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) and morpholine following the procedure for the preparation of Compound 200. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH2:12]C(N)=O>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:12]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc(Cl)cc1Br
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cc1Br

Procedure:
588 mg of 2-bromo-4-chlorobenzoic acid and 300 mg of urea are dissolved in dichloromethane/methanole and deposited onto 364 mg of aluminum oxide on a rotary evaporator. The residue is irradiated for 60 min in a microwave at 150° C. After cooling the residue is stirred with ethyl acetate and water, the mixture is filtered and the aqueous phase is removed. The organic phase is washed with a sodium hydrogencarbonate solution dried over sodium sulfate, concentrated on a rotary evaporator and then dried under high vacuum. The product is reacted further without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:15][N:14]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:15][N:14]=1
Reactant: COc1ccc2c(Cl)nnc(-c3ccccc3)c2c1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-c3ccccc3)c2c1
Yield: 46.9 %

Procedure:
Operating as described in example 5 starting from 3,5-dichloro-4-methyl-pyridine (0.45 g, 2.81 mmoles) in dry DMF (10 ml), 60% NaH (67 mg, 2.81 mmoles) and 1-chloro-6-methoxy-4-phenyl-phthalazine (0.38 g, 1.4 mmoles), prepared as described in example 14, in DMF (10 ml), 0.26 g of the title compound were obtained (yield: 47.3%). m.p.: 206-208° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]2)[CH2:28][O:27]1>>[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH:37][C:13](=[O:15])[CH:12]([N:8]3[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=4[F:1])[CH:6]=[N:7]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:33]2)[CH2:28][O:27]1
Reactant: CC(C)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 28) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as an off-white solid as a mixture of diastereoisomers (1.21 g, 79%); ES+-HRMS m/e calcd for C25H29N5O5F2 [M+H+] 518.2210 found 518.2214. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.25 (s, 3H), 1.30, 1.31 (2×s, 3H), 1.38-1.51 (m, 1H), 1.74-1.85 (m, 1H), 2.12-2.24 (m, 1H), 3.74 (dd, J=8.4, 5.9 Hz, 1H), 3.97-4.17 (m, 3H), 4.35 (m, 1H), 5.52 (dd, J=11.2, 4.2 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.35-7.43 (m, 2H), 7.43-7.55 (m, 1H), 7.60 (m, 1H), 8.28 (d, J=2.7 Hz, 1H), 10.85 (s, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:24])[NH:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[C:14]([N+:21]([O-])=O)[CH:13]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:24])[NH:11][C:12]1[CH:13]=[C:14]([NH2:21])[CH:15]=[C:16]([NH2:18])[CH:17]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OCCOC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCCOC(=O)Nc1cc(N)cc(N)c1
Temperature: 20 °C
Reaction time: 1.17 h

Procedure:
4.8 g of 5% palladium carbon, 48.0 g (0.141 mol) of 2-(3,5-dinitrophenylcarbamoyloxy)ethyl isobutyrate (compound 8) and 700 ml of ethanol were placed in a 5-l autoclave equipped with a thermocouple thermometer and a mixing blade, and the autoclave was sealed. The atmosphere inside the autoclave was replaced by hydrogen and the hydrogen pressure was raised to 5 kg/cm2. The autoclave contents were stirred at room temperature (20° C.). Ten minutes later, the autoclave inside temperature rose to 34° C. and the autoclave inside pressure dropped to 1 kg/cm2. Then, hydrogen was introduced to raise the pressure to 5 kg/cm2, and stirring was continued. 20 minutes later, the temperature became 30° C. and the pressure dropped to 2.5 kg/cm2. Hydrogen was again introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Since the temperature began to drop and the pressure became constant (3 kg/cm2), stirring was continued for 70 minutes (the temperature dropped to 23° C.). The atmosphere inside the autoclave was replaced by nitrogen, and the autoclave contents were taken out and filtered to remove palladium carbon. The filtrate was concentrated by the use of an evaporator. The resulting concentrate was placed under reduced pressure by the use of a rotary pump to distil off the solvent to obtain 2-(3,5-diaminophenylcarbamoyloxy)ethyl isobutyrate (compound 9) as a brown viscous liquid. Yield: 33.7 g (85%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Br[C:28]1[N:29]=[CH:30][NH:31][CH:32]=1.C(NCC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:30]2[NH:29][CH:28]=[CH:32][N:31]=2)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2)c1
Reactant: Brc1c[nH]cn1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C#Cc2ncc[nH]2)cc1-c1ccccc1
Temperature: 25 °C

Procedure:
The resultant product from Example 47A (5 mmol) is mixed with 4-bromoimidazole (5 mmol), diethylamine (1 mL), bis(triphenylphosphine) palladium diacetate (0.1 mmol) and copper(I) iodide (0.1 mmol) in toluene. The mixture is stirred at 25° C. until TLC analysis indicates the reaction is complete. The reaction mixture is concentrated in vacuo, and the residue is purified with column chromatography on silica gel to give the title product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.CC[N:16](CC)CC.N>C1COCC1>[NH2:16][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:12][CH3:13])[N:5]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCN(CC)CC
Agent: N
Solvent: C1CCOC1
Product: CSc1nc(N)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (327 mg, 1.36 mmol) in THF (5.4 mL) at −10° C. was added Et3N (474 μL, 3.40 mmol) followed by a solution of NH3 (2.0 M in MeOH, 750 μL, 1.5 mmol). The mixture was stirred while warming to 0° C. for 1.5 h (LC/MS indicated consumption of starting materials.). The reaction mixture was taken forward without work-up.
Reaction SMILES: [NH3:1].C(Cl)Cl.[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](Cl)(=[O:20])=[O:19])=[O:11])[CH2:6]1>O>[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([NH2:1])(=[O:20])=[O:19])=[O:11])[CH2:6]1
Reactant: N
Reactant: O=C(OC1COC1)c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1C(=O)OC1COC1

Procedure:
2.5 g of ammonia are passed into a methylene chloride solution of 2-(oxetan-3-oxycarbonyl)phenylsulfonyl chloride (Example H6) at a temperature of 0° to 5° C. in the course of 45 minutes. By adding water to the reaction mixture, washing the organic phase with water, drying and evaporating it and crystallising the residue from a methylene chloride/diethyl ether mixture, 6.7 g of 2-(oxetan-3-oxycarbonyl)phenylsulfonamide of melting point 169° to 170° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[CH:26][C:27](Br)=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:32]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:49][C:48]2[CH:50]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:52]=[CH:53][C:47]=2[N:46]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([C:51]5[CH:52]=[CH:53][C:47]6[N:46]=[C:45]([CH:41]7[CH2:42][CH2:43][CH2:44][N:40]7[C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:39])[NH:49][C:48]=6[CH:50]=5)=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:32]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc(Br)ccc2-3)[nH]1
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc(-c4ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 90 °C
Yield: 29.9 %

Procedure:
To the solution of 2-[5-(3-Bromo-6H-benzo[c]chromen-8-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (9 mg, 0.02 mmol) and 2-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (9.6 mg, 0.02 mmol) in DME (0.75 ml) and water (0.25 ml) was added potassium carbonate (10 mg, 0.07 mmol), followed by Pd(PPh3)4 (2 mg) and PdCl2(dppf)CH2Cl2 (2 mg). The mixture was heated at 90° C. for 6 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 2-(5-{3-[2-(1-t-butoxycarbonyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-6H-benzo[c]chromen-8-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.2 mg). m/z: 729.2 (M+1), 727.3 (M−1), 365.2 (M+2)/2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].NC(N)=[S:17].C(O)C.[OH-].[Na+]>O>[SH:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: NC(N)=S
Reactant: O=C(O)CCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCCCCCS
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.46 %

Procedure:
A mixture of 200 g of 11-bromoundecanoic acid, 60 g of thiourea and 600 mL of absolute ethanol was stirred and heated at reflux for two hours. After heating was stopped a solution of 80 g of sodium hydroxide in 250 mL of water was then added dropwise. The mixture was held overnight and then heated at reflux for three hours. After cooling to room temperature a solid precipitated from solution. The reaction mixture was poured into a mixture of ice and 200 g of concentrated hydrochloric acid. The solids were filtered from solution then slurried with ice water, isolated by filtration and washed twice. The off-white solid was stored in a crystallizing dish for one week, then dried under vacuum (~1 mm of Hg) at about 45° C. The product was distilled under vacuum (~1 mm of Hg at ~160° C). NMR analysis indicated the desired product was obtained. The distilled product weighed 74.7 g representing 45.46% yield based upon the weight of starting 11-bromoundecanoic acid.