Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].Br[CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53].O>CN(C)C=O>[F:42][C:40]([F:43])([F:41])[C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:33])[CH3:34])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)nc1
Reaction time: 0.08 h

Procedure:
6-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-ol (141 mg) is dissolved in N,N-dimethylformamide (1 ml), and thereto is added 60% sodium hydride (10 mg) under ice-cooling and the mixture is stirred for 5 minutes and thereto is added ethyl 4-bromobutyrate (48 μl), and the mixture is stirred at room temperature for 1 hour. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-{6-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (154.1 mg). MS (m/z): 757 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCCC(c2cccc3ccc(N)cc23)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCCC(c2cccc3ccc(NC(=O)c4ccccc4)cc23)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A mixture of 7-amino-1-(1-methyl-3-piperidinyl)-naphthalene (0.203 g, 0.845 mmol, product of example 61) and triethylamine (0.141 mL, 1.01 mmol) in tetrahydrofuran (5 mL) was chilled to 0° C. and benzoyl chloride (0.118 mL, 1.01 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The reaction was concentrated at reduced pressure and the residue was taken up in methylene chloride. The organic phase was extracted with 0.5N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×2 inches). Elution proceeded as follows: 50% ethyl acetate/hexane (225 mL), 75% ethyl acetate/hexane (150 mL) nil; 75% ethyl acetate/hexane (400 mL) and ethyl acetate (200 mL) 0.198 g of pink foam. This product was converted to an HCl salt in methanol, treated with activated carbon, and filtered. The filtrate was concentrated and triturated with ether to give 0.091 g (31%) of the title compound as an amorphous solid with a melting range of 140°-170° C. 1H NMR (DMSO d6) δ 10.59 (s, 1 H), 10.34 (br s, 1 H), 8.73 (s, 1H), 8.06 (d, J=7 Hz, 2 H), 7.94 (distorted t, J=10 Hz, 2 H), 7.82 (d, J=7 Hz, 1H), 7.63-7.53 (m, 3 H), 7.47-7.39 (m, 2 H), 3.78 (br t, J=12 Hz, 1 H), 3.56 (br t, J=11 Hz, 2 H), 3.05 (br s, 1 H), 2.83 (br s, 3 H), 2.15-1.97 (m0 2 H), 1.71 (br s, 1 H). HRMS m/e calculated for C23H24N2O; m/e 344.1883. Observed m/e 344.1886.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36][C@@H]1CCNC1)=O)(C)(C)C.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Product: Cl
Product: Nc1ncc(Br)c2c(S(=O)(=O)N3CC[C@@H](N)C3)cccc12

Procedure:
(R)-3-(tert-Butoxycarbonylamino)-1-(1-chloro-4-bromo-5-isoquinolinesulfonyl)pyrrolidine can be prepared by using (R)-3-(tert-butoxycarbonylamino)pyrrolidine in the method of Example 35-1, Step A instead of (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, and then the protective group of the obtained compound can be removed according to the method described in Example 39-1, Step B to obtain the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:14]([CH3:13])[O:15][CH2:16][C:17]([OH:19])=[O:18])=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)ccc1NC(=S)N(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of 4-chloro-2-methylphenyl-isothiocyanate (12.8 g), N-methyl aminooxy acetic acid hydrochloride (10 g), triethylamine (7.5 g) and chloroform (100 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (200 mL) and extracted with sodium bicarbonate saturated solution (2×200 mL). The aqueous extract was acidified with 6N HCl and extracted with ethyl acetate (2×300 mL). The organic phase was washed with water (200 mL), dried over anhydrous magnesium sulfate and evaporated to dryness to give 13.9 g of [[[[(4-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as a solid, m.p. 110-113° C. Mass spectrum (El, M.+) m/z 288/290. 1H-NMR (DMSO-d6; 400 MHz) δ□13.20 (br s, 1H), 10.12 (s, 1H), 7.34-7.19 (m, 3H),4.69 (q, 2H), 3.55 (s, 3H), and 2.17 ppm (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13](C(O)=O)[NH:12]2)=[O:10])=[CH:4][CH:3]=1.C[N:25]([C:32]1C=CC(N)=CC=1)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[CH2:39]([Cl:42])[CH2:40]Cl>CN(C=O)C>[CH3:32][N:25]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH:11]2[CH2:20][C:15]3[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][N:12]2[C:9]([NH:8][C:5]2[CH:6]=[CH:40][C:39]([Cl:42])=[CH:3][CH:4]=2)=[O:10])=[O:10])=[CH:6][CH:7]=1)[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1
Reactant: O=C(O)C1Cc2ccccc2C(C(=O)Nc2ccc(Cl)cc2)N1
Reactant: CN(c1ccncc1)c1ccc(N)cc1
Reactant: ClCCCl
Solvent: CN(C)C=O
Product: CN(c1ccncc1)c1ccc(NC(=O)C2Cc3ccccc3CN2C(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 2N-(4-chlorophenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (63 mg, 0.19 mmol) and 4-(N-methyl-N-pyridin-4-yl-amino)phenylamine (47 mg, 0.24 mmol) in DMF (3 mL), EDC (80 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (25 mg). MS 512.2 and 514.2 (M+H, Cl pattern).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH3:28].C(O)(=O)/C=C/C(O)=O>C(#N)C>[CH2:27]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[C:6]([F:17])=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)[CH3:28]
Reactant: CCI
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.70 g, 2.54 mmol), acetonitrile (30 ml), potassium carbonate (0.35 g) and 2-iodoethane (0.40 g. 2.54 mmol). Yield: 0.21 g (27%). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether: M.p. 109-110° C. MS m/z (rel. intensity, 70 eV) 303 (M+, 13), 302 (10), 289 (16), 288 (bp), 234 (7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br>>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: COC(=O)c1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: COC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 76 %

Procedure:
Methyl 2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (Example 100) (16.15 g, 56.0 mmol) and 2,6-difluorobenzyl bromide (14.67 g, 70.86 mmol, 125 M %) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding white crystals of methyl 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (17.63 g, 42.55 mmol, 76% yield). M.p. 184-186° C. 1H NMR (200 MHz, CD2Cl2): δ 7.94 (dd, J=1.1, 7.6 Hz, 1H, H5), 7.72 (dd, J=1.1, 8.2 Hz, 1H, H7), 7.56 (m, 1H, H4′), 7.37 (dd, J=7.6, 8.2 Hz, 1H, H6), 7.26 (m, 1H, H4″), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.39 (s, 2H, CH2PhF2), 3.95 (s, 3H, CO2CH3).
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][NH:10][C:11](=O)OC(C)(C)C)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1(CCNC(=O)OC(C)(C)C)CCNCC1.Br[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=2)[N:38]=[CH:37][C:36]=1[F:47].BrC1C(F)=CN=C2C=1N=C(OC)C=C2.[O:62]=[C:63]1[CH2:68][O:67][C:66]2[CH:69]=[CH:70][C:71](C=O)=[N:72][C:65]=2[NH:64]1.O=C1CSC2C=CC(C=O)=NC=2N1>>[F:47][C:36]1[CH:37]=[N:38][C:39]2[C:44]([C:35]=1[N:5]1[CH2:4][CH2:3][C:2]([CH2:8][CH2:9][NH:10][CH2:11][C:71]3[CH:70]=[CH:69][C:66]4[O:67][CH2:68][C:63](=[O:62])[NH:64][C:65]=4[N:72]=3)([OH:1])[CH2:7][CH2:6]1)=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(F)c(Br)c2c1
Reactant: CC(C)(C)OC(=O)NCCC1(O)CCNCC1
Agent: CC(C)(C)OC(=O)NCCN1CCNCC1
Agent: COc1ccc2ncc(F)c(Br)c2n1
Agent: O=Cc1ccc2c(n1)NC(=O)CS2
Product: COc1ccc2ncc(F)c(N3CCC(O)(CCNCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 26.1 %

Procedure:
The title compound (71 mg, 26%) was prepared as a yellow solid according to Example 1, except substituting the following three reagents: 1,1-dimethylethyl [2-(4-hydroxy-4-piperidinyl)ethyl]carbamate (1.5 g, 6.15 mmol) [prepared according to Example 20] for 1,1-dimethylethyl [2-(1-piperazinyl)ethyl]carbamate, 4-bromo-3-fluoro-6-(methyloxy)quinoline (1.57 g, 6.15 mmol) for 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (100 mg, 0.564 mmol) for 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde: LCMS (ES) m/e 482 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=4.6 Hz, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.33 (dd, J=2.7, 6.3 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.65 (s, 2H), 3.96 (s, 3H), 3.81 (s, 3H), 3.55-3.61 (m, 2H), 3.26-3.29 (m, 2H), 2.88-2.91 (m, 2H), 1.80-1.93 (m, 6H).
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7][C:6]=2[C:5]([O:14][CH3:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]1.C(Cl)Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:15][O:14][C:5]1[C:6]2[CH2:7][CH2:8][CH:9]([N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]3)[CH2:10][CH2:11][C:12]=2[CH:2]=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: OC1CCCNC1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2c1CCC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCCC(O)C1)CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.00 g, 0.00637 mol) and piperidin-3-ol (6 g, 0.06 mol) in methylene chloride (100 mL, 2 mol) at room temperature was added acetic acid (4 mL, 0.06 mol) dropwise. Molecular sieves (2 mass equiv) were added to the reaction mixture and the contents heated at 40° C. overnight. The reaction mixture was cooled to room temperature then at 0° C. in an ice bath. Sodium triacetoxyborohydride (7 g, 0.03 mol) was added in one portion as a solid. The reaction mixture continued to stirr at 0° C. for 1 h then warmed to room temperature for 4 h Workup involved quenching with water, adjusting the pH to 8-10 with 10 N NaOH (aq) and extracting with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a dark oil. Purification involved ISCO chromatography on silica gel (40 g column) using methylene chloride-methanol with 5% ammonium hydroxide. Fractions corresponding to product (polar fractions) were combined and concentration to give 1-(1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-piperidin-3-ol as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 3.86 (s, 4H), 3.47 (m, 3H), 2.88 (t, 1H, J=11 Hz), 2.60-2.70 (m, 4H), 2.48-2.41 (m, 2H), 2.21 (m, 2H), 1.86 (m, 2H), 1.59 (m, 3H), 1.26-1.39 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
2-(Butyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (9.45 g) was dissolved in chloroform (50 ml) and cooled to 0° C. (ice-bath). To this solution was added portion wise N-bromosuccinimide (6.07 g) keeping the temperature below 3° C. This gave a dark green solution, stirred at 2.5° C. for 30 mins. before allowing to warm to room temperature and then stirring for 6 hours. The reaction mixture was then washed with water (100 ml, twice). Organic phase was dried/separated using a hydrophobic frit and evaporated to give a dark brown gum which was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-50% ethyl acetate:cyclohexane to afford the title compound as a pale yellow solid (8.37 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
A 3-neck flask was charged with 3-nitro-4-phenylaminobenzoic acid (see Synthesis Example 1-1) (1.67 g, 6.70 mmol), palladium/carbon (Pd:10%, 0.170 g), and tetrahydrofuran (34 mL), the atmosphere was replaced with hydrogen using three cycles of vacuum/hydrogen purge, and this was stirred at room temperature for 2.5 hours. After substituting in nitrogen, distilled water (20 mL) was added and this was stirred for 10 minutes, insoluble material was filtered off through a Celite layer (20 mm thickness), and this same layer was further washed with tetrahydrofuran (20 mL, 3 times). The filtrate and the wash solutions were combined, and the solvent was distilled off under reduced pressure. This was successively extracted with ethyl acetate (approx. 50 mL, 4 times), washed with distilled water (30 mL), and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and further drying under reduced pressure yielded the title compound (1.45 g, 95.3% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[Cl:27][CH2:28][C:29]([CH2:31]Cl)=[O:30]>CN(C=O)C>[CH3:7][C:2]([S:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[CH:12][C:11]=1[O:20][CH3:21])([CH3:1])[CH2:3][C:4]([O:6][CH2:31][C:29](=[O:30])[CH2:28][Cl:27])=[O:5]
Reactant: COc1cc(OC)c(CSC(C)(C)CC(=O)O)c(OC)c1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(CSC(C)(C)CC(=O)OCC(=O)CCl)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
To a mixture of 3-methyl-3-[(2,4,6-trimethoxyphenyl)methylthio]butanoic acid (3 g, 9.54 mmol) and sodium bicarbonate (975 mg, 11.6 mmol) in DMF (30 mL) was added a solution of 1,3-dichloroacetone (4.23 g, 33.4 mmol) in DMF (15 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature, and stirred for 48 hours. The residue after evaporation of the solvent was partitioned between EtOAc and H2O. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel eluting with EtOAc:Hex (20-30%) to give the title compound as a yellow oil (2.19 g, 57%). 1H NMR (300 MHz, CDCl3) δ 6.12 (s, 2H), 4.87 (s, 2H), 4.21 (s, 2H), 3.86-3.80 (mult, 11H), 2.83 (s, 2H), 1.52 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.5, 170.1, 160.4, 158.6, 107.3, 90.7, 66.4, 55.8, 55.3, 46.3, 45.9, 43.8, 28.2, 20.9; mass spectrum (API-TIS) m/z 422 (M+NH4).
Reaction SMILES: C(O)(=O)C.[NH2:5][C@@H:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[C:13]([O:15][CH3:16])=[O:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:5][C@@H:6]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[C:13]([O:15][CH3:16])=[O:14])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H]1CCCCC[C@H]1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 25.9 %

Procedure:
A solution of trans-methyl 2-aminocycloheptanecarboxylate acetate (652 mg, 2.82 mmol), 4-chlorobenzene sulfonyl chloride (893 mg, 4.23 mmol), and triethylamine (1.18 mL, 8.46 mmol) was stirred in 20 mL tetrahydrofuran for 2 h. The reaction was partitioned between 100 mL diethyl ether and 100 mL brine. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography on 40 g silica gel with 15 to 40% ethyl acetate in hexane to yield trans-methyl 2-(4-chlorophenylsulfonamido)cycloheptanecarboxylate (253 mg, 26%). 1H NMR (400 MHz, CDCl3) δ ppm 7.77-7.79 (1H, m), 7.74-7.76 (1H, m), 7.44-7.47 (1H, m), 7.42-7.44 (1H, m), 5.21 (1H, d, J=8.56 Hz), 3.68 (1H, qd, J=8.48, 3.78 Hz), 3.43 (3H, s), 2.44 (1H, td, J=8.56, 3.27 Hz), 1.75-1.82 (1H, m), 1.56-1.73 (4H, m), 1.34-1.54 (5H, m). LC/MS R.T.=2.89 min; [M−H]+=344.04; [M+Na]+=368.16; [M−H]−=344.04.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][CH2:40][NH2:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:41]4[CH2:40][CH2:39][C@@H:35]5[CH2:36][CH2:37][CH2:38][N:34]5[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: NCC[C@@H]1CCCN1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCc1ccc(F)cc1)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1CC[C@@H]3CCCN3[C@@H]1C2
Yield: 128.1 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (84 mg, 0.13 mmol) and {2-[(2S)-2-Pyrrolidinyl]ethyl}amine (150 mg, 1.3 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3aS,13aS)—N-[(4-fluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide (86 mg, 90%). This material was hydrogenated in a second step as described in example Z-2 to give (3aS,13aS)—N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:3,4]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide. (63 mg, 88%) as a white solid. 1H NMR (CDCl3/CD3OD) δ 10.45 (m, 1H), 8.23 (s, 1H), 7.35 (m, 2H), 6.94 (t, J=8.8 Hz, 2H), 4.63 (m, 1H), 4.58-4.48 (m, 2H), 4.33 (dd, J=13.6, 3.6 Hz, 1H), 4.21 (m, 1H), 4.11 (m, 1H), 2.98 (m, 1H), 2.85 (td, J=13.2, 3.2 Hz, 1H), 2.41 (m, 1H), 2.29 (m, 1H), 1.92 (m, 1H), 1.83-1.75 (m, 3H), 1.54-1.35 (m, 2H); ES+ MS: 427 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]([CH3:37])[C@H:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:29][CH2:28]1>>[CH:27]1([N:30]([CH3:37])[C@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32]2)[CH2:29][CH2:28]1
Reactant: CN(C1CC1)[C@H]1CCCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@H](N(C)C4CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-cyclopropyl-N-methylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.68-1.16 (m, 4H) 1.49-1.68 (m, 1H) 1.71-2.00 (m, 2H) 2.17-2.30 (m, 1H) 2.43 (s, 3H) 2.91 (d, J=12.38 Hz, 4H) 3.18 (br. s., 1H) 3.56 (br. s., 2H) 3.91-4.58 (m, 1H) 4.79 (br. s., 1H) 7.67 (d, J=7.83 Hz, 1H) 7.71-7.86 (m, 2H) 8.00-8.28 (m, 2H) 8.57 (s, 2H) 9.53 (br. s., 1H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([NH2:14])[CH3:13].[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19](Cl)=[O:20])([CH3:17])[CH3:16]>O1CCCC1>[CH:15]([C:18]([CH3:25])([CH:22]([CH3:24])[CH3:23])[C:19]([NH:14][CH:12]([C:8]1[O:7][CH:11]=[CH:10][CH:9]=1)[CH3:13])=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)C(C)(C(=O)Cl)C(C)C
Reactant: CC(N)c1ccco1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(NC(=O)C(C)(C(C)C)C(C)C)c1ccco1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
In a 25 mL round bottom flask, fitted with magnetic stirrer, 15 mL of tetrahydrofuran, 2.1 mmol (1.5 eq.) of pyridine and 1.54 mmol (1.1 eq.) of 1-(furan-2-yl)ethanamine were added. 1.4 mmol of 2-isopropyl-2,3-dimethylbutanoyl chloride (prepared by hydrolysis of 2-isopropyl-N,2,3-trimethylbutanamide, WS-23 with NaNO2 in H2SO4 and subsequent acid chloride formation with SOCl2) were added and the mixture was stirred at room to temperature for 16 hours, overnight. The reaction mixture was extracted with MTBE and HCl (1N in water). The organic layer was washed with NaOH (1N in water) and brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography, obtaining 160 mg of a beige solid, mp 57-60° C.