Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[N:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][C:4]=1[F:28])[CH3:2].ClS([N:33]=[C:34]=O)(=O)=O>CN(C=O)C.C(#N)C>[C:34]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[C:4]([F:28])[CH:5]=2)[NH:9][C:8]=1[C:12]1[N:17]=[CH:16][C:15]([S:18]([NH:21][C@@H:22]([CH3:27])[C:23]([F:25])([F:26])[F:24])(=[O:19])=[O:20])=[CH:14][CH:13]=1)#[N:33]
Reactant: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn3)cc2cc1F
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1cc2[nH]c(-c3ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn3)c(C#N)c2cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-6-(6-ethyl-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (0.22 g, 0.53 mmol) in a mixture of DMF (0.5 mL) and acetonitrile (0.5 mL) was added chlorosulfonyl isocyanate dropwise at −50° C. The reaction mixture was kept stirring at 0° C. for 0.5 hr and then quenched with ice, following by pouring into water. After 0.5 hr stirring at room temperature, the resulting solid was collected by filtration and washed with water, hexane and CH2Cl2. After air drying, (S)-6-(3-cyano-6-ethyl-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:42]([CH3:44])[CH3:43])[C:31]4[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=4)=[O:29])[C:23]4[CH:45]=[CH:46][CH:47]=[CH:48][C:22]=4[N:21]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:20]3=[O:55])=[N:7][N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH:19]3[C:25](=[O:26])[N:24]([CH2:27][C:28]([N:30]([CH:42]([CH3:44])[CH3:43])[C:31]4[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=4)=[O:29])[C:23]4[CH:45]=[CH:46][CH:47]=[CH:48][C:22]=4[N:21]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:20]3=[O:55])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Reaction time: 6 h
Yield: 65.8 %

Procedure:
70 mg of 2-[3-(6-Fluoro-1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-trifluoromethoxy-phenyl)-acetamide, prepared as in Intermediate 70, is dissolved in 2 mL of CHCl3 and 5 mL of TFA is added. The reaction mixture is stirred for 6 h and the solvents were removed in vacuo. The residue is purified by silica gel flash column chromatography using hexane/EtOAc 40:60 as eluent to afford the 40 mg of the title compound: 1H NMR (400 MHz, DMSO-d6) δ7.73 (dd, 1H, J=8.9, 5.1), 7.41-7.18 (m, 12H), 7.08 (dd, 1H, J=7.3, 2.0), 6.97 (dd, 1H, J=8.9, 1.7), 6.92 (dd, 1H, J=7.2, 2.0), 6.84 (dd, 1H,J=9.1, 2.0), 5.01 (m, 1H), 4.22 (m, 3H), 3.75 (dd, 1H, J=16.5, 6.4), 3.56 (dd, 1H, J=16.5, 6.4), 1.06 (t, 6H, J=6.8); low resolution MS (FAB) m/e 660 (MH+); Tr =12.32 min. (HPLC Column: Dynamax C-8 2 mL/min., 50-90% Acetonitrile in aqueous TFA (0.1% v/v) over 15 min.).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][CH:8]([CH3:15])[CH2:9][CH2:10][P+](C)(C)C.[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])[CH:20]=O.CN(C)C=O>CCOCC>[Cl:16][CH2:17][CH2:18][C@H:19]([CH3:22])/[CH:20]=[CH:10]\[CH2:9][CH:8]([CH3:15])[CH3:7]
Reactant: C[C@H](C=O)CCCl
Reactant: CC(C)CC[P+](C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C/C=C\[C@@H](C)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
23.5 ml of n-butyllithium (about 2-M in n-hexane) are added dropwise under argon to a suspension of 20.4 g of 3-methylbutyl-trimethylphosphonium bromide in 80 ml of dry ether, a reaction temperature of about 20° being adhered to by slight cooling. Thereafter, the mixture is stirred at room temperature for a further 2 hours. The mixture is cooled to -10° and a solution of 5.4 g of (S)-4-chloro-2-methylbutyraldehyde in 5 ml of dry ether is added thereto. The separated precipitate is stirred for one hour without cooling bath, whereupon 100 ml of dimethylformamide are added dropwise at room temperature. The mixture is stirred at room temperature for 16 hours, hydrolysed on ice and extracted with ether. The ether phase is washed with water, dried and concentrated under reduced pressure. The residue is purified by adsorption on silicagel as well as on neutral aluminium oxide of the activities III and II (elution agent: n-hexane). After distillation under reduced pressure (13 mm Torr/90°), there are obtained 4.13 g (53%) of (S)-cis-1-chloro-3,7--dimethyl-4-octene. [α]D20 =+32.6° (2.15% in chloroform).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[OH2:21].C(Cl)Cl>N1CCOCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:3]3[CH2:4][CH2:5][O:21][CH2:7][CH2:2]3)[CH:7]=2)=[O:9])=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: O
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1[N+](=O)[O-]
Solvent: C1COCCN1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
2-Chloro-N-(4-methyl-3-nitrophenyl)pyridine-4-carboxamide (18.33 g) was stirred in morpholine (250 ml) at 100° C. for 18 hours. Reaction was poured into water (250 ml) affording a gummy solid. Methylene chloride (30 ml) was added and stirred for 30 minutes and solid filtered, washed with methylene chloride and dried in a vacuum oven for 18 hours to yield N-(4-methyl-3-nitrophenyl)-2-morpholinopyridine-4-carboxamide the title compound (17.34 g); NMR: 2.48 (s, 3H), 3.52 (m, 4H), 3.71 (m, 4H), 7.1 (d, 1H), 7.25 (s, 1H), 7.49 (d, 1H), 7.97 (m, 1H), 8.29 (m, 1H), 8.49 (m, 1H), 10.62 (s, 1H); m/s: M+H+ 343.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42]>>[ClH:1].[CH3:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reactant: COCCOCCBr
Agent: Cl
Product: COCCOCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 52 %

Procedure:
Using methods analogus to those previously described, compound 11 (0.4 mmol) is reacted with 1-bromo-2-(2-methoxyethoxy)ethane to afford the title compound 60 (0.21 mmol, 52%) as a hygroscopic white solid: 1H NMR (CDCl3) δ 9.4 (br, 1H), 8.5 (br, 1H), 8.32 (br, 1H), 7.54 (s, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.56 (s, 1H), 6.47 (m, 2H), 4.34 (v br, water H), 4.1 (m, 4H), 3.83 (m, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.38 (s, 3H), 2.96 (hept, J=7 Hz, 1H), 2.8–2.6 (m, 5H), 2.4–2.2 (m, 3H), 2.15 (s, 3H), 1.80 (m, 2H), 1.6 (m, 1H), 1.5–1.3 (m, 3H), 1.27 (d, J=7 Hz, 6H); MS (CI) m/z 559.5 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([N:52]2[CH2:67][CH2:66][C:55]3[N:56]=[CH:57][N:58]=[C:59]([O:60][C@H:61]4[CH2:65][CH2:64][NH:63][CH2:62]4)[C:54]=3[CH2:53]2)=[CH:48][C:47]=1[C:68]([F:71])([F:70])[F:69]>CN(C=O)C>[CH3:44][O:45][C:46]1[N:51]=[CH:50][C:49]([N:52]2[CH2:67][CH2:66][C:55]3[N:56]=[CH:57][N:58]=[C:59]([O:60][C@H:61]4[CH2:65][CH2:64][N:63]([C:6]([C:4]5[N:3]=[CH:2][O:1][CH:5]=5)=[O:8])[CH2:62]4)[C:54]=3[CH2:53]2)=[CH:48][C:47]=1[C:68]([F:71])([F:69])[F:70]
Reactant: O=C(O)c1cocn1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5cocn5)C4)c3C2)cc1C(F)(F)F
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
To the oxazole-4-carboxylic acid (27 mg, 0.24 mmol)) and HBTU (89 mg, 0.24 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.45 mmol). The mixture was stirred for 20 min and then 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (100 mg, 0.214 mmol) and additional N,N-diisopropylethylamine (0.08 mL, 0.45 mmol) were added. The mixture was allowed to stir at room temperature for 30 min. Purified by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone as a yellow solid (38 mg, 36% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.11-2.39 (m, 2 H) 2.80-3.01 (m, 2 H) 3.22-4.29 (m, 11 H) 5.59-5.80 (m, 1 H) 7.72-7.94 (m, 1 H) 8.10-8.29 (m, 1 H) 8.41-8.55 (m, 1 H) 8.57-8.77 (m, 2 H) LCMS: [M+H]+=491.1, Rt(1)=1.69 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([OH:15])=O.[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[NH:11][C@H:12]([C@@H:16]([OH:18])[CH3:17])[C:13]([NH:28][NH:27][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1Cl)C(=O)NNC(=O)c1ccccc1
Yield: 49.7 %

Procedure:
(2R,3S)-2-(2,3-dichloro-4-cyanophenylamino)-3-hydroxybutanoic acid (1.0 g, 3.46 mmol) and benzohydrazide (471 mg, 3.46 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (700 mg, 50%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.7 (br s, 2H), 7.91 (d, J=8 Hz, 2H), 7.41-7.62 (m, 4H), 6.82 (d, J=8 Hz, 1H), 6.18 (d, J=7 Hz, 1H), 4.90 (br s, 1H), 4.38-4.41 (m, 1H), 4.19-4.21 (m, 1H) and 1.32 (d, J=6 Hz, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[N+]=[N-].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(CCOCCOCCN=[N+]=[N-])OCC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCOCCOCCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 2-(2-(2-azidoethoxy)ethoxy)ethylphosphonate (1 eq) was dissolved in EtOH (0.1 M). Pd(OH)2 (0.05 eq) was added to the reaction. Hydrogen gas was introduced via a balloon; and the reaction was stirred for 2 hours at room temperature. The mixture was filtered through Celite and washed with MeOH. The solvent was removed en vaccuo and the crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM with 0.5% NH3 to give diethyl 2-(2-(2-aminoethoxy)ethoxy)ethylphosphonate as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][N:9]([NH2:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([OH:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[OH:25][C:19]1([C:15]2[N:14]=[C:13]([CH2:12][N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:3]=4[NH:10][N:9]3[NH2:11])[CH:18]=[CH:17][CH:16]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: OB(O)c1ccccc1
Reactant: NN1Nc2c(Cl)ncnc2N1Cc1cccc(C2(O)CCOCC2)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NN1Nc2c(-c3ccccc3)ncnc2N1Cc1cccc(C2(O)CCOCC2)n1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A solution of the 7-chloro-3-(6-[4-hydroxytetrahydropyran-4-yl]pyridine-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-2-amine (0.10 g, 0.27 mmol) and phenylboronic acid (0.05 g, 0.41 mmol) and potassium phosphate (0.12 g, 0.55 mmol) in 1,4-dioxane (5 mL) was degassed by sparging with nitrogen. Tetrakis triphenylphosphine palladium (16 mg) was then added, the solution degassed again and the resultant mixture heated at 100° C. for seven hours. The mixture was then concentrated onto Isolute-HM in vacuo, purified by column chromatography (silica, eluting with 3:1 ethyl acetate:hexane and neat ethyl acetate) and triturated with diethyl ether to give the title compound (41 mg, 37%) as a pale beige solid.
Reaction SMILES: [CH:1]12[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]1[S:4][CH:3]=[CH:2]2.B(O[O-])=[O:13].O.[Na+].O>O1CCCC1>[OH:13][C@H:2]1[CH:1]2[CH:5]([C@@H:6]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1C2C=CSC21
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C2SC[C@@H](O)C21
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (6S)-4-thiabicyclo[3.1.0]hex-2-ene-6-carboxylate (22.2 g, 131 mmol) in 136 mL of tetrahydrofuran under nitrogen at 0° C. is added borane-THF complex (98 mL, 98 mmol) over 15-20 minutes. After stiffing at 0° C. for 30 minutes, the reaction is allowed to warm to 15° C. and stir until complete by HPLC (1.5-2 hours). The reaction is cooled to 0° C. and transferred over 10-15 minutes to 111 mL of a pre-cooled (0° C.) 1 N pH 7 buffer solution while maintaining the temperature at 0° C. To the mixture is added sodium perborate monohydrate (15.6 g, 157 mmol) as a solid in five portions such that the temperature is maintained below 20° C. The solution is allowed to warm to room temperature and stir for 1 hour followed by the addition of 222 mL of water. After stirring for 2 hours, the peroxides are quenched by adding sodium thiosulfate pentahydrate (9.7 g) dissolved in 24 mL of water followed by stirring for 10 minutes. The mixture is extracted with ethyl acetate (2×222 mL). The combined organic extracts are washed with saturated aqueous sodium bicarbonate (1×222 mL) followed by brine (1×222 mL) and concentration in vacuo to dryness. The crude product is dissolved in 1,2-dichloroethane (1 mL per 1 g of crude oil) and loaded onto a silica gel column (4 g of silica gel per 1 g of crude oil slurried and packed in 15% ethyl acetate-heptane). The column is eluted with 15% ethyl acetate-heptane until product is visible by TLC, at which time the solvent is switched to 50% ethyl acetate-heptane. All fractions containing the title product are combined and concentrated in vacuo to an oil. Overall yield is in the 55-65% range.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16](O)=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].C[N:21]1CCOCC1.ClC(OCC)=O>O1CCCC1.C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH2:21])=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(N)=O)NC1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.30 g, 1.05 mmol) is dissolved in tetrahydrofuran (5.0 mL). 4-Methylmorpholine (0.14 mL, 1.05 mmol) is then added, and the reaction is cooled to -20° C. Ethyl chloroformate (0.1 mL, 1.05 mmol) is then added, and the reaction is stirred at -20° C. for 30 minutes. The reaction is then filtered, and the filtrate is concentrated to give a yellow oil. This oil is dissolved in methylene chloride (20.0 mL), and anhydrous ammonia gas is bubbled through the solution for 1 hour. The bubbling is stopped, and the reaction is stirred an additional 1 hour. The solvent is evaporated, and the residue is partitioned between ethyl acetate and water. The aqueous layer is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxamide, MS:M+1=287.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.[CH3:17][C:18]1([CH3:35])[O:22][C@H:21]([CH2:23]OS(C2C=CC(Cl)=CC=2)(=O)=O)[CH2:20][O:19]1.CC(C)([O-])C.[Na+].O>O1CCOCC1>[CH3:17][C:18]1([CH3:35])[O:22][C@H:21]([CH2:23][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)[CH2:20][O:19]1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: CC1(C)OC[C@@H](COS(=O)(=O)c2ccc(Cl)cc2)O1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC[C@@H](Cn2ccc(N3C(=O)c4ccccc4C3=O)n2)O1
Temperature: 103 °C
Yield: 74 %

Procedure:
A mixture of 2-(1H-pyrazol-3-yl)-isoindole-1,3-dione (5.00 g, 23.5 mmol), 4-chloro-benzenesulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl ester (8.00 g, 26.1 mmol), and sodium t-butoxide (2.78 g, 28.9 mmol) in 1,4-dioxane (50 mL) was refluxed (103° C.) for 24 h. Upon cooling to 25° C., water (55 mL) was added. The mixture became cloudy and crystallization was observed. Then, water (50 mL) was slowly added over 30 min. Subsequent filtration, washing with water, and suction drying provided 2-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-isoindole-1,3-dione (5.69 g, 74.1%) as an off-white solid: LR-ES-MS m/z calculated for C17H17N3O4 [M]+ 327, observed [M+H]+ 328.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].Cl[C:19]([O:21][CH2:22][CH2:23][Cl:24])=[O:20]>COCCOCCOC.O>[Cl:24][CH2:23][CH2:22][O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc(NC(=O)OCCCl)cc1[N+](=O)[O-]
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
420.5 g of 4-amino-2-nitroanisole are dissolved in 1275 ml of diethylene glycol dimethyl ether and 150 ml of water, 135 g of calcium carbonate are added and the mixture is heated to 78° C. 375 g of 2-chloroethyl chloroformate are allowed to run into this mixture in the course of 3 hours such that the reaction temperature remains at 78°-80° C. The mixture is subsequently stirred for 1.5 hours to bring the reaction to completion and is cooled to 35° C. and water and ice are added. The product which has precipitated is filtered off, washed with water and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](I)[CH2:28][CH3:29].O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:27][CH2:28][CH3:29])[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 26.7 %

Procedure:
A solution of benzyl 4-[(tert-butoxycarbonyl)amino]piperidine-1-carboxylate obtained in Example (241a) (1.00 g, 2.99 mmol) in THF (5 mL) was added to a suspension of sodium hydride (55%) (261 mg, 5.98 mmol) in THF (25 mL) at 0° C. Subsequently, propyl iodide (1.46 mL, 15.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 22 hours. Thereafter, sodium hydride (55%) (130 mg, 2.99 mmol) and propyl iodide (0.58 mL, 5.98 mmol) were added, and the mixture was heated under reflux for 22 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Thereafter, the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1) to obtain 301 mg of the title compound as a pale yellow oily substance (27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1

Procedure:
2-chloro-4-fluoronitrobenzene (1.0 eq, 1 g, 5.7 mmol), N-methyl piperazine (1.2 eq, 1.18 g, 6.84 mmol), potassium carbonate (2.0 eq, 1.6 g, 11.6 mmol) were stirred at 100° C. in DMF for 3 hours. The mixture was cooled down and diluted with water. The material was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. After trituration in diethylether and filtration, 1-(3-chloro-4-nitrophenyl)-4-methylpiperazine was isolated as a solid (0.9 g, 62%). LCMS (ES): m/z 256 [M+1]+. This material was suspended in MeOH (20 ml) with Raney Nickel (0.2 g) and stirred under hydrogen atmosphere overnight. The catalyst was filtered off through celite. Evaporation of the solvents provided 2-chloro-4-(4-methylpiperazin-1-yl)aniline as a dark brown oil (0.68 g, 86%). LCMS (ES): m/z 226 [M+1]+.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:12]=[CH:13][C:14]=1[CH2:15]O.C(N(CC)CC)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH2:43]([N:50]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([NH:17][C:18]([C:20]3[C:21]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:10]=2)[CH2:15]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Nc1ccc(CO)c(CCO)c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCN(Cc1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 39 %

Procedure:
Methanesulfonyl chloride (0.041 mL) was added to a 0° C. solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide (100 mg, 0.24 mmol) and triethylamine (0.084 mL) in THF (2 mL). TLC showed complete reaction after 30 min. Benzylamine (0.132 mL) was added and the contents stirred for 18 hrs at 25° C. and 60 hrs at 50° C. The solvent was removed under vacuum, the residue dissolved in methylene chloride (15 mL), washed with pH9 buffer, phases separated, and the organic phase dried with magnesium sulfate. Removal of the solvent under vacuum gave the crude product as a white solid (204 mg), which was repulsed in CDCl3 filtered off and dried to give the product as a white solid (46 mg, 39%). mp=230-32° C.