Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].CO.C(Cl)(Cl)Cl>C(COC)OC.C1COCC1.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]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:27]4[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
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: [Na+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4cc(F)cc(F)c4)c3c2CC1
Yield: 100 %

Procedure:
A mixture of 3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.923 g, 2.5 mmol) and tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol) in dimethoxyethane (10.0 mL) and a solution of 3,5-difluorophenylboronic acid (0.95 g of a 50% by weight solution in THF/H2O, 3.0 mmol) and sodium carbonate (2 M, 12.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 1-5% MeOH/CHCl3) afforded 1.03 g (100%) of a white solid: mp 198-201° C.; 1H NMR (400 MHz, CDCl3) δ 8.32, 7.40-7.28, 7.14, 6.98-6.80, 6.80-6.70, 4.04-3.94, 3.83-3.73, 3.65-3.58, 3.60-3.50, 3.20-3.13, 2.94-2.84, 2.71-2.60,2.45-2.36; R (drift) 3235, 3211, 1607, 1466, 1431, 1336, 1291, 1117, 984, 864, 789, 751, 737, 704, 698 cm−1; MS (EI) m/z 402 (M+); Anal. Calcd for C25H20F2N2O: C, 74.61; H, 5.01; N, 6.96. Found: C, 74.57; H, 5.05; N, 6.99.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([OH:41])[CH2:36]2.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[OH:41][N:37]1[C:38](=[O:40])[C:39]2[C:35](=[CH:34][CH:33]=[CH:32][C:31]=2[NH:30][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)[CH2:36]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: Nc1cccc2c1C(=O)N(O)C2
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(O)C4)n2)c(OC)c1)OCC
Yield: 7 %

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.11 mmol) and 7-amino-2-hydroxy-2,3-dihydro-1H-isoindol-1-one (Compound 186A, 21.70 mg, 0.13 mmol). The reaction mixture purified by MDP to isolate the desired product (4.6 mg, yield: 7%) as a TFA salt. 1H NMR (CD3OD, 400 MHz): δ=1.29 (t, J=7.2 Hz, 6 H), 3.33 (d, J=21.2 Hz, 2 H), 3.89 (s, 3 H), 4.06-4.13 (m, 4 H), 4.63 (s, 2 H), 4.96 (dt, J=2.8, 8.4 Hz, 1 H), 7.10 (t, J=2.0 Hz, 1 H), 7.24 (d, J=7.6 Hz, 1 H), 7.36 (dd, J=0.8, 8.0 Hz, 0.5 H), 7.52 (m, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 8.32 (d, J=8.0 Hz, 0.5 H), 8.37 (s, 1 H). MS (ES+): m/z 582.17 [MH+]. HPLC: tR=3.64 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][NH2:7].[NH2:9][C:10]1[C:11]([C:18](N2C=CN=C2)=[O:19])=[N:12][C:13]([Br:17])=[C:14]([NH2:16])[N:15]=1>O1CCCC1>[NH2:9][C:10]1[C:11]([C:18]([NH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH2:7])[CH3:8])=[O:19])=[N:12][C:13]([Br:17])=[C:14]([NH2:16])[N:15]=1
Reactant: CN(CCN)CCN
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Br
Solvent: C1CCOC1
Product: CN(CCN)CCNC(=O)c1nc(Br)c(N)nc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A mixture of 8.20 g (72.0 mmol) of N-(2-aminoethyl)-N-methyl-1,2-ethanediamine and 6.80 g (24.0 mmol) of 1-(3,5-diamino-6-bromopyrazinoyl)imidazole in 48 ml of tetrahydrofuran was stirred at ambient temperature for 30 minutes. The solution was evaporated and the residue triturated with ether. There was obtained 5.85 g (17.6 mmol, 73%) of 3,5-diamino-N-[2-[(2-aminoethyl)methylamino]ethyl]-6-bromopyrazinecarboxamide; mp 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29](/[CH:32]=[C:8]2/[C:9](=[O:12])[C:10]3[C:6]([CH2:7]/2)=[CH:5][C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\C1CCN(Cc3ccccc3)CC1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 1-benzylpiperidine-4-carbaldehyde 21 (123.4 mg, 0.607 mmol). p-Toluene sulphonic acid (PTSA) (230.9 mg, 1.214 mmol) was added to the reaction mixture, and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude material, which was purified through flash chromatography using 100-200 mesh silica gel. Eluting at 30% ethyl acetate in hexane gave yellow coloured solid (E)-2-((1-benzylpiperidin-4-yl)methylene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 22.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4C)CC3)nc2c1
Yield: 90 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.35 (s, 3H), 2.95-3.02 (m, 4H), 3.75-3.90 (m, 6H), 4.09-4.13 (m, 4H), 6.99-7.31 (m, 7H), 7.50-7.66 (m, 1H).
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[F:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:52]=1[C:53](O)=[O:54]>>[F:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:52]=1[C:53]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@:33]1([CH3:32])[NH:39][C:40]1[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=1)=[O:54]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: O=C(O)c1c(F)cccc1F
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1c(F)cccc1F

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 63 mg, 0.24 mmol) and 2,6-difluorobenzoic acid (CAS number 385-00-2; 46 mg, 0.29 mmol) except this was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([C@:6]1([CH3:51])[C@@H:45]([C:46]([OH:48])=[O:47])[C@@:44]2([CH3:49])[C@@:9]([CH3:50])([C@@H:10]3[C:41](=[CH:42][CH2:43]2)[C@@:14]24[CH2:21][C@@H:20]([N:22]5[C:26]([C:27]6[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=6)=[N:25][CH:24]=[N:23]5)[C@H:19]([O:33][CH2:34][C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)[C@@:18]([CH3:40])([C@@H:13]2[CH2:12][CH2:11]3)[CH2:17][O:16][CH2:15]4)[CH2:8][CH2:7]1)[CH:3]([CH3:5])[CH3:4].C=O.[CH3:54]C(O)=O.C([BH3-])#N.[Na+]>CO.C1COCC1>[CH3:1][C@@H:2]([C@:6]1([CH3:51])[C@@H:45]([C:46]([OH:48])=[O:47])[C@@:44]2([CH3:49])[C@@:9]([CH3:50])([C@@H:10]3[C:41](=[CH:42][CH2:43]2)[C@@:14]24[CH2:21][C@@H:20]([N:22]5[C:26]([C:27]6[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=6)=[N:25][CH:24]=[N:23]5)[C@H:19]([O:33][CH2:34][C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5[CH3:54])[C@@:18]([CH3:40])([C@@H:13]2[CH2:12][CH2:11]3)[CH2:17][O:16][CH2:15]4)[CH2:8][CH2:7]1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(=O)O
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@@H]4CCCN4)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@@H]4CCCN4C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-15-[(2S)-2-pyrrolidinylmethoxy]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 304; 98 mg, 0.14 mmol) in MeOH (6.0 mL) were added sequentially 30% (wt/wt) aqueous formaldehyde (126 mg, 4.21 mmol), HOAc (200 μL) and sodium cyanoborohydride in (448 μL of a 1.0 M solution in THF, 0.45 mmol). The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and water and this mixture was extracted with 10% i-PrOH in CH2Cl2. The combined organic extracts were then dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by RP HPLC (0.1% TFA water/methanol gradient) to provide the title compound (38 mg, 38%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(=O)O)ccc2C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Bromo-4-trifluoromethyl-benzoic acid (0.484 g, 1.80 mmol), 3-chloro-4-methoxy-phenylboronic acid (0.503 g, 2.70 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.313 g, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.494 g, 0.54 mmol) and potassium fluoride (0.345 g, 5.93 mmol) were weighed into a flask and dioxane (10 ml) was added under argon, and the mixture was stirred for 24 h at 50° C. The mixture was filtered over celite and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8]C(N)=[N:10][C:5]2=[CH:4][CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].C(O)=O>[OH-].[Na+]>[NH2:10][C:5]1[C:6]([SH:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Nc1nc2ccc(Cl)nc2s1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Nc1ccc(Cl)nc1S
Temperature: 25 °C

Procedure:
5-Chlorothiazolo[5,4-b]pyridin-2-amine (Q-2) (19 g, 103 mmol) containing sodium sulfite (2 g) was refluxed in 20% aqueous sodium hydroxide solution (150 mL) overnight. The solids were completely dissolved after 1 h, then cooled to room temperature. The solution was neutralized with formic acid. A precipitate was collected by filtration as the title compound (16.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][C:12]([OH:14])=[O:13]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)CBr
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
100 g 4-Aminobenzonitrile and 234.7 g bromoacetic acid in 1400 mL water were stirred for 15 min in round bottom flask. The reaction mixture was heated to 100° C. and maintained for 16 hours. The reaction mixture was cooled to 10° C. and stirred for 2 hours. The reaction mixture was filtered and washed with water to obtain 2-(4-cyanophenylamino) acetic acid of Formula (D).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[N:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH3:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][N:10]2[N:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1ncnn1)c1ccc(Cl)cc1
Reactant: CCCCBr
Product: CCCCOC(=Cn1ncnn1)c1ccc(Cl)cc1

Procedure:
Analogously to Example 7a,b, after reacting 1-(4-chlorophenyl)-2-tetrazol-2-yl-ethanone with n-butyl bromide there was obtained 2-[2-(4-chloro-phenyl)-2-butoxy-vinyl]-2H-tetrazole as a colourless oil. [M+H]+ =279.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([CH:35]=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(CO)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCn1cc(C=O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 76.1 %

Procedure:
To a yellow solution of 1-ethyl-6-fluoro-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy) quinolin-4(1H)-one (33 g, 66.9 mmol) in Dichloromethane (DCM) (200 mL) was added manganese dioxide (58.1 g, 669 mmol), and the mixture was stirred at rt for 6.5 h. The mixture was then filtered through Celite and the solid was washed with DCM. The filtrate was concentrated in vacuo to afford 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (25 g, 50.9 mmol, 76% yield) as a yellow solid, which was used in the next step without further purification. LCMS: (M+H)+: 492.3.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([CH3:26])[CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([CH3:26])[C:12]([CH2:16]/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(Br)cc(C)c1C/C=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)cc(C)c1C/C=C/C(=O)O
Reaction time: 4 h
Yield: 100.3 %

Procedure:
TFA (10 mL) was added to a solution of 53B (2.35 g) in CH2Cl2 (20 mL) at 0° C. and stirred for 4 h. The reaction mixture was concentrated to yield 53C (1.95 g, 99%) as an off-white solid. MS (ESI) m/z 267.2/269.2 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(OC(=O)C2CCCc3ccc([N+](=O)[O-])cc32)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54.2 %

Procedure:
In 20 ml of pyridine were dissolved 1 g of 7-nitro-1,2,3,4-tetrahydro-1-naphthoic acid and 560 mg of p-methoxyphenol. To the solution which had been cooled was added 700 mg of phosphorus oxychloride and the mixture was allowed to stand for 2 days. The reaction mixture was poured into ice water, made slightly alkaline with a 5% sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and concentrated under reduced pressure to remove the ethyl acetate. The residue was recrystallized from an ethyl acetate-hexane mixture to obtain 0.8 g of p-methoxyphenyl 7-nitro-1,2,3,4-tetrahydro-1-naphthoate, m.p. 109°-110° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:27]#[N:28])([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:43][C@@H:42]([CH2:44][CH2:45][NH2:46])[CH2:41][O:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:43][C@H:42]([CH2:41][OH:40])[CH2:44][CH2:45][NH:46][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:27]#[N:28])([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17]1)=[O:35]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Yield: 55.3 %

Procedure:
In a manner similar to the method described in Example 42e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 55c (0.4 g, 0.73 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.4 mmol), HATU (0.3 g, 0.8 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 55%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.CI.[C:28](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C(=O)/C=C/c2cn(C)c3ccccc23)cc(OC)c1OC
Yield: 81.6 %

Procedure:
Compound 1 (1.0 g) obtained in Example 1 was dissolved in acetone (50 ml), and methyl iodide (1.42 g) and potassium carbonate (1.0 g) were added thereto, followed by heating under reflux for 72 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate (20 ml) in a condition of heating under reflux, and insoluble matters were filtered off. Hexane (25 ml) was added to the filtrate, and the precipitated crystals were collected by filtration to give Compound 2 (0.85 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[O:5])C.[OH-].[Li+]>>[F:22][C:20]([F:21])([F:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([CH:9]1[CH2:8][N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:10]1)(=[O:12])=[O:13]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 253e, 4-(2-trifluoromethyl-benzenesulfonyl)-1-(3-trifluoromethyl-phenyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as white solid which was used in the next step without further purification. MS (ESI): m/z=468.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([O:40]C)=O)=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:54][NH2:55]>C(O)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:35]([CH3:45])=[CH:36][C:37]([C:38]([NH:54][NH2:55])=[O:40])=[CH:42][C:43]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:49][CH:48]([F:50])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:4]=[C:3]([C:2]([F:52])([F:1])[F:53])[CH:8]=1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: NN
Solvent: CCO
Product: COc1ncc(-c2c(C)cc(C(=O)NN)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (EXAMPLE 32 Step A, 0.091 g, 0.122 mmol) was dissolved in ethanol (0.80 mL). Added hydrazine (0.115 mL, 3.65 mmol) and stirred at 85° C. in a screw cap vial (with a pressure relief cap) under a nitrogen blanket. The reaction was monitored by LCMS. Once complete the reaction was cooled to room temperature. The solvent was removed by rotary evaporation and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.15 (s, 1H), 8.00 (d, 1H), 7.88 (s, 1H), 7.74 (s, 2H), 7.51 (d, 2H), 7.43 (s, 1H), 7.27 (d, 1H), 5.70 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.69 (d, 1H), 4.45 (m, 3H), 4.29 (m, 2H), 3.99 (m, s, 4H), 2.14 (s, 3H), 2.13 (s, 3H), 1.65 (br, 2H), 0.74 (d, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[S:10]([CH:13]([CH3:17])[C:14](=O)[CH3:15])[C:11]#[N:12]>>[ClH:9].[Cl:9][C:6]1[N:7]=[CH:8][C:3]([N:2]2[C:14]([CH3:15])=[C:13]([CH3:17])[S:10][C:11]2=[NH:12])=[CH:4][CH:5]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CC(=O)C(C)SC#N
Agent: Cl
Product: Cc1sc(=N)n(-c2ccc(Cl)nc2)c1C

Procedure:
The title compound was prepared from 5-amino-2-chloropyridine hydrochloride and 3-thiocyano-2-butanone as described for Example 160A.