Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15]C1CC(C(C)C)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1

Procedure:
The bromination of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].N1C=CC=CC=1.[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:21]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Combine 3-nitroaniline (3.0 g, 21.7 mmol), dichloromethane (100 mL), pyridine (2.11 mL, 26.0 mmol) and 2-chloro-4-fluorobenzoyl chloride (3.07 mL, 23.9 mmol). Stir at room temperature overnight. Filter the white precipitate, rinse with ether (2×10 mL), and dry under vacuum to provide 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g, 77%). Combine the 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g, 16.7 mmol) with ethanol (150 mL), SnCl2.2H2O (18.9 g, 83.6 mmol) and concentrated hydrochloric acid (8.24 mL, 83.6 mmol). Stir at reflux under a nitrogen atmosphere for 2 hr. Neutralize with ammonium hydroxide (15 mL). Filter through celite, wash with dichloromethane (2×15 mL), separate the filtrate, extract with dichloromethane (2×80 mL), and dry the combined organic layers over magnesium sulfate. Filter and concentrate to dryness to provide the title intermediate as an off-white solid (3.04 g, 69%): mass spectrum (ion spray): m/z=265.0(M+1); 1H NMR (DMSO-d6): 10.16 (bs, N—H), 7.60 (dd, J=6.2 Hz, 8.6 Hz, 1H), 7.54 (dd, J=2.5 Hz, 9.0 Hz, 1H), 7.30 (td, J=2.5 Hz, 8.5 Hz, 1H), 7.04 (t, J=2.0 Hz, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.74 (bd, J=7.9 Hz, 1H), 6.29 (dd, J=2.2 Hz, 7.9 Hz, 1H), 5.10 (bs, 2H).
Reaction SMILES: [CH:1]1([C:7]2[S:17][C:10]3[N:11]=[C:12]([CH3:16])[NH:13][C:14](=O)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>CN(C=O)C>[Cl:27][C:14]1[C:9]2[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:17][C:10]=2[N:11]=[C:12]([CH3:16])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2sc(C3CCCCC3)cc2c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Temperature: 150 °C

Procedure:
To a mixture of 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (25.0 g) and toluene (300 mL) were added phosphorous oxychloride (14 mL) and DMF (200 μL), followed by heating to reflux at 150° C. for 14 hours. The reaction mixture was left to be cooled to room temperature and concentrated under reduced pressure. To the residue were added chloroform, water, and saturated aqueous sodium bicarbonate, followed by stirring. The reaction mixture was extracted with chloroform. The organic layer was washed sequentially with water and brine. To the organic layer were added MgSO4, activated carbon (2 g), and silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (27.4 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([CH3:23])[O:20][N:19]=2)[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2].FC1C=C(C=CC=1F)CNC(C1C2C(=CC(OC(C)C)=CC=2)N(CC2OC=CN=2)C=1C(C)C)=[O:31]>>[CH:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([CH3:23])[O:20][N:19]=2)[C:6]2[C:11]([C:12]=1[C:13]([OH:31])=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C=O)c(C(C)C)n(Cc3cc(C)on3)c2c1
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1
Product: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3cc(C)on3)c2c1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carbaldehyde (Compound 213) by General Procedure K.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C1(O)C=CC=CC=1.[OH:14][C@@H:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CC1C=CC(S(O[CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][S:47][CH2:46]2)(=O)=O)=CC=1>CN(C=O)C>[OH:14][C@@H:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][S:47][CH2:46]2)[CH:27]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCSC2)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCCSC2)c1
Temperature: 100 °C

Procedure:
K2CO3 (0.72 g, 5.24 mmol) and phenol (7, Intermediate I) (0.3 g, 1.05 mmol) were added to a solution of (tetrahydro-2H-thiopyran-3-yl)methyl 4-methylbenzenesulfonate (0.29 g, 1.10 mmol) in DMF (10 mL). The reaction mixture was heated at 100° C. under reflux overnight and then cooled. The reaction mixture was extracted with EtOAc, organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:hexane 10-40% gradient) gave tert-butyl ((3R)-3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propyl)carbamate as a light green solid. Yield (0.21 g, 52%); 1H NMR (400 MHz, CDCl3): δ 7.24 (t, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 2H), 6.78 (d, 1H), 4.87 (bs, 1H), 4.71 (bs, 1H), 3.84-3.80 (m, 2H), 3.49 (bs, 1H), 3.21-3.13 (m, 2H), 2.82-2.77 (m, 1H), 2.62-2.47 (m, 3H), 2.18 (bs, 1H), 2.08-2.04 (m, 1H), 1.91-1.74 (m, 4H), 1.45 (s, 9H), 1.30-1.20 (m, 3H); MS: m/z 382.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)c2ncccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc(C(F)(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of tert-butyl 2-(8-(trifluoromethyl)quinolin-5-yl)acetate (400 mg, 1.28 mmol) in DCM (5 mL) was added TFA (10 mL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was removed and the residue was purified (silica gel chromatography) to give the final product 2-(8-(trifluoromethyl)quinolin-5-yl)acetic acid (180 mg, 54%). LC-MS (0.05% TFA): [M+1]+ 256.1. 1H-NMR (DMSO-d6, 400 MHz): δ 12.70 (s, 1H), 9.07(m, 1H), 8.56 (m, 1H), 8.15 (d, 1H), 7.74(m,1H), 7.68 (m,1H), 4.23(s, 2H). 13C-NMR (DMSO-d6, 100MHz): 67 171.9, 151.0, 144.0, 138.3, 133.5, 127.87, 127.83, 127.78, 125.3, 123.1, 122.2, 37.7.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[Br-].[CH2:31]([Zn+])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:31]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1CCCOc1cccc2ccccc12
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cc2ccccc2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 31C (100 mg), 0.5M benzyl zinc(II) bromide in THF (1.32 mL) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (18 mg) in THF (2 mL) was stirred at 60° C. for 16 hours. The mixture was diluted with ethyl acetate, and the organic phase was washed with water and brine and dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-8% ethyl acetate/hexanes.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CBr
Reactant: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Temperature: 0 °C

Procedure:
In a three-necked round bottom flask equipped with mechanical stirring and nitrogen inlet was placed methyl bromacetate (7.82 mL, 82.6 mmol) and a suspension of N4 -benzyloxycarbonyl-cytosine (9, 21 g, 82.6 mmol) and potassium carbonate (11.4 g, 82.6 mmol) in dry DMF (900 mL). The mixture was stirred vigorously overnight, filtered, and evaporated to dryness, in vacuo. Water (300 mL) and 4N hydrochloric acid (10 mL) were added, the mixture was stirred for 15 minutes at 0° C., filtered, and washed with water (2×75 mL). The isolated precipitate was treated with water (120 mL), 2N sodium hydroxide (60 mL), stirred for 30 minutes, filtered, cooled to 0° C., and 4N hydrochloric acid (35 mL) was added. The title compound was isolated by filtration, washed thoroughly with water, recrystallized from methanol (1000 mL) and washed thoroughly with ether. This afforded 7.70 g (31%) of pure title compound. The mother liquor from recrystallization was reduced to a volume of 200 mL and cooled to 0° C. This afforded an additional 2.30 g of a material that was pure by tlc but had a reddish color. M.p. 266°-274° C. Anal. for C14H13N3O5. Found(calc.); C: 55.41 (55.45); H: 4.23(4.32); N: 14.04(13.86). 1H-NMR (90 MHz; DMSO-d6): 8.02 ppm (d,J=7.32 Hz, 1H, H-6); 7.39 (s, 5H, Ph); 7.01 (d, J=7.32 Hz, 1H, H-5); 5.19 (s, 2H, PhCH2 --); 4.52 (s, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CC([O-])(C)C.[K+].C(O)=O>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[Cl:18]
Reactant: Clc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)N(c1ccc(Cl)cc1)c1nc2ccccc2s1
Yield: 67 %

Procedure:
A mixture of 39.1 mg (0.15 mmol) Benzothiazol-2-yl-(4-chloro-phenyl)-amine in 0.5 ml THF, 45.2 mg (0.18 mmol) 2-chlorobenzoyl chloride in 0.18 ml THF and 0.17 ml of a 1 M solution of KOtBu in THF was heated to 50° C. for 16 h. After addition of 0.5 ml formic acid the mixtures are subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 40.1 mg (67%) of the title compound. MS (m/e): 399.3 (MH+, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1[F:39].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][C:66]=1[O:73][CH3:74]>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[C:10]([F:39])[CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:66]([O:73][CH3:74])[CH:67]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)c(F)cc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 47 (0.7 g, 1.2 mmol), was reacted with diisopropylethylamine (0.78 g, 6.0 mmol), diphenylphosphinic chloride (0.57 g, 2.4 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.54 g, 3.6 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.24 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][CH2:8][C:9]3([O:16]2)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:5][C:4]=1[NH2:19].CS([C:23]1[N:28]=[CH:27][C:26]2=[CH:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:25]2[N:24]=1)=O>>[CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][CH2:8][C:9]3([O:16]2)[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[CH:5][C:4]=1[NH:19][C:23]1[N:28]=[CH:27][C:26]2=[CH:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])[N:25]2[N:24]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: COc1cc2c(cc1N)CCC1(CCN(C)CC1)O2
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n1)CCC1(CCN(C)CC1)O2
Yield: 0.2 %

Procedure:
Following a procedure analogous to 251c, 7-methoxy-1′-methyl-3,4-dihydrospiro[chromene-2,4′-piperidin]-6-amine (0.15 g, 57 mmol) and N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (69 mg, 19 mmol) were converted to the title compound (23 mgs, 18%) isolated as a TFA salt. H-NMR (DMSO-d6) δ 9.49 (broad s, 1H), 8.92 (s, 1H), 7.94 (s, 1H), 7.65 (s, 2H), 7.69-7.66 (m, 3H), 6.98-6.94 (m, 2H), 6.52 (s, 1H), 3.80 (s, 3H), 3.39-3.31 (m, 2H), 3.23-3.13 (m, 2H), 3.06 (s, 3H), 2.87-2.81 (m, 7H), 2.55-2.51 (m, 2H), 2.00-1.91 (m, 2H), 1.84-1.76 (m, 32H); LC/MS (ESI+): 563.17 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>C(O)(=O)C.CO>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCCn1ccnc1
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Yield: 170.1 %

Procedure:
A solution of 3-imidazol-1-yl-propylamine (6 μL, 0.036 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (30 mg, 0.08 mmol) in 0.5 mL of acetic acid was heated to 110° C. for 0.5 hour. After cooling to room temperature, the mixture was dissolved in 2 mL of methanol and loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 26 mg of 8-Cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.49 (s, 1H), 7.57 (br, 1H), 7.09 (br, 1H), 6.96 (br, 1H), 6.10 (br, 1H), 5.02 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.11 (t, J=6.6 Hz, 2H), 3.51 (br, 2H), 2.20-1.50 (m, 8H), 1.40 (t, J=7.2 Hz, 3H), 1.26 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H28N6O3: 425.22 (M+H). Found: 425.2.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:9]=1[S:19](=[O:22])(=[O:21])[NH2:20])=O.[OH-].[Na+].Cl>>[CH3:18][S:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:5]([CH2:4][C:3]([OH:2])=[O:23])=[N:20][S:19](=[O:22])(=[O:21])[C:9]=2[CH:10]=1)(=[O:17])=[O:16]
Reactant: COC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Temperature: 23 °C
Reaction time: 30 h
Yield: 87 %

Procedure:
N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid methyl ester (prepared as described in Example 1g, 1.35 kg, 3.69 mol) was added to 3.8 wt. % aqueous sodium hydroxide solution (14.0 kg). The resulting mixture was stirred at 23° C. for 30 h, and was then cooled to 0° C. A 2.0 M aqueous hydrochloric acid solution (9.72 L) was slowly added, stirring at 0° C. was continued for 30 min, and the mixture was then filtered. The solid was washed with water (1.4 L), and was then slurried in a mixture of methanol (1.4 L) and diethyl ether (2.7 L). After filtration, the solid was washed with diethyl ether (2×1.4 L) and was further dried in vacuo at 23° C. to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (1.07 kg, 3.21 mol, 87%), as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N
Reactant: O=C(O)C1CCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3C(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 89b) and cyclohexanecarboxylic acid as brown solid (46%). MS 440 (MH+).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11](=[O:29])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NC1CCCCC1)c1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Product: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Yield: 76 %

Procedure:
A solution of Compound 7 (0.7 g, 1.77 mmol) in 20 mL neat phosphorus oxychloride was heated at 90° C. for 2 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 420 mg (76%) of white solids. M.P. 231° C. 1H NMR (DMSO-d6): δ 5.54 (s, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.80 (t, J=8.4 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H). EIMS m/z 335 (M+23). Anal. (C17H10ClFN2O) C, H, N.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:18])[CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C1COCC1.O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:9](=[O:18])[C@@H:10]([OH:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: CCNCC
Reactant: O=C(ON1C(=O)CCC1=O)C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)[C@@H](O)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of the hydroxy-phenyl-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.70 g, 2.8 mmol) in THF/H2O (10 mL, 1:1) was added diethylamine (25% in H2O, 0.58 mL, 5.6 mmol). After stirring for 16 h, the reaction solvent was evaporated under reduced pressure. The resulting residue was diluted with H2O and extracted with EtOAc (3×50 mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:30][CH:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:33]([CH:31]([CH3:32])[CH3:30])(=[O:35])=[O:34])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C(F)(F)F)ccc3N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.47 mmol) in pyridine (0.23 mL, 2.81 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of propane-2-sulfonyl chloride (200 mg, 1.40 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford propane-2-sulfonic acid [3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (155 mg, 77.8%) as a white solid. MS (ESI+APCI) M+1=427.2.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][N:12]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)(C)C>CO>[C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: O=C(O[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(benzoyloxy)-5-(tert-butyl-dimethylsilyloxy)-piperidine-1-carboxylate (1 eq) in 30 mL of methanol was added 3.8M HCl in isopropanol (4 eq). The reaction mixture was allowed to stand at room temperature for 3 hours at which point it was concentrated under reduced pressure. The resulting residue was diluted with 120 mL of EtOAc, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to yield (3S,5R)-benzyl 3-(benzoyloxy)-5-hydroxypiperidine-1-carboxylate (95%). LC/MS (m/z): 355.9 (MH+). HPLC: Rt:3.62 min.