Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29](=[O:40])[CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:23]1.N1CCCCC1>C(O)C>[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29](=[O:40])[CH2:30][C:31]2[C:32]([CH3:39])=[C:33](/[CH:37]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:34][C:35]=2[CH3:36])[CH2:23]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1C[C@@H](C)N[C@@H](C)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 4-[2-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (184 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with acetone to give the titled compound as a pale orange-red solid.
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].Cl.C(N(CC)CC)C.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[N:15]1([CH:3]=[CH:4][C:5]#[N:6])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: N#CC=CO
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CC=CN1CCCCC1
Temperature: 25 °C
Yield: 79 %

Procedure:
30.3 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 75%) is added to a suspension of 41.3 g (0.3 mol) of triethylamine hydrochloride and 21.3 g (0.25 mol) of piperidine in 200 ml of ethanol and maintained for 24 h at 25° C. After working up as in Example 56, 26.9 g of 3-piperidinoacrylonitrile is obtained (79.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cccc(N3CCOCC3)c21
Product: CC1c2c(cccc2N2CCOCC2)CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[NH:17][CH:16]2[C:35](O)=[O:36])[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:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:18]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[NH:17]1)=[O:36]
Reactant: N#CC1(c2ccc(Cl)cc2)C(C2CCCCC2)NC(C(=O)O)C1c1cccc(Cl)c1
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: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2)C(C2CCCCC2)NC(C(=O)NCC[C@H](O)CO)C1c1cccc(Cl)c1
Yield: 62 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 50c (0.5 g, 0.76 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.9 g, 7 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,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.25 g, 62%).
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH:11]([CH3:13])[CH3:12])[N:3]=1.[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19]([C:2]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]([CH:11]([CH3:13])[CH3:12])[N:3]=2)=[CH:18][CH:17]=1
Reactant: CC(C)n1nc(Br)c2ncccc21
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(C(C)C)c3cccnc23)cn1
Yield: 89.5 %

Procedure:
To a mixture of 3-bromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine (100 mg), 6-methoxypyridin-3-ylboronic acid (96 mg), Pd(OAc)2 (9.35 mg), and Xphos (39.7 mg) in THF (3 mL) was added a solution of Cs2CO3 (271 mg) in H2O (1 mL). The mixture was exposed to microwave irradiation at 100° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C3CCCCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(Cl)c(NC(=O)C2CCCCC2)c1
Yield: 13.6 %

Procedure:
To a solution of methyl 2-(4-chloro-3-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (380 mg, 0.835 mmol) in methanol (15 mL) was added a solution of sodium hydroxide (270 mg, 6.68 mmol) in water (6.8 mL). The mixture was stirred and heated to reflux for 5 h. The mixture was evaporated, and the residue was dissolved in 15 mL of water. The aqueous solution was acidified to pH=3 with 1M hydrochloric acid. The precipitated solid was collected by filtration, and dissolved in ethyl acetate. The organic layer was dried over sodium sulfate. After evaporation, the mixture was purified on silica gel to afford 50 mg of 2-(4-chloro-3-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as an off white solid. (Yield: 14%) MS(ESI+APCI) M+1=423.2, M−1=441.0.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2>>[F:34][C:32]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2)=[C:24]([O:23][CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:11]3[C:6]4[O:5][CH2:4][C:3](=[O:19])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:14][CH2:15]2)[CH:33]=1
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Reactant: Cc1ccc2c(OCCBr)cc(F)cc2n1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cc(F)cc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-fluoro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])/[CH:17]=[CH:18]/[CH3:19].C1(N(C)C2CCCCC2)CCCCC1>[Cl-].C([N+](CC)(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[F:13][C:12]([F:15])([F:14])[CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[C:18](/[CH3:19])=[CH:17]/[C:16]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][CH:4]=1
Reactant: C/C=C/C(=O)OCC
Reactant: FC(F)(F)CCCOc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C(\C)c1ccc(OCCCC(F)(F)F)cc1
Temperature: 110 °C
Yield: 57.6 %

Procedure:
Intermediate 11A (2.81 g, 9.93 mmol), (E)-ethyl but-2-enoate (1.25 g, 10.9 mmol), palladium(II) acetate (0.11 g, 0.5 mmol), tetraethylammonium chloride (1.65 g, 9.9 mmol), N-cyclohexyl-N-methylcyclohexanamine (2.91 g, 14.9 mmol) and dimethylacetamide (30 ml) were placed in a oven-dried vial and sparged with argon for 5 min. The vial was sealed and the reaction heated to 110° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (75 mL), washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes to provide Intermediate 11B (1.81 g, 49%) as a colorless oil. LCMS Anal. Calc'd for C16H19F3O3 316.32, found [M+H] 317.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(F)(F)F)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:34][CH2:33][CH:32]([C:29]3[S:30][CH:31]=[C:27]([C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[N:28]=3)[CH2:37][CH2:36]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(-c2csc(C3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(F)(F)F)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N2CCC(c3nc(-c4ccc(F)cc4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A mixture of 2,2,2-trifluoroethyl [6-(acetylamino)pyridin-3-yl]carbamate (274 mg, 0.839 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (193 mg, 57.6%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:17]=[C:16]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43].ClCCl>O>[NH:1]([C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[N:17]=[C:16]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:42]([CH3:43])=[O:44]
Reactant: Nc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
5-(3′-Amino-biphenyl-4-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (8.0 mg, 0.02 mmol) prepared in Example 253, pyridine (2.2 uL, 0.02 mmol) and acetyl chloride (1.4 uL, 0.02 mmol) were added at 0° C. to dichloromethane (0.3 mL). The reaction mixture was stirred at room temperature for 2 hours and then distilled water was added thereto. The reaction mixture was extracted with dichloromethane two times. The combined extract was washed with a 1N hydrochloric acid solution, a saturated solution of sodium carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 1.9 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:9][C:8]=1[F:25])[CH3:2].P(Br)(Br)[Br:28]>ClCCl.O>[Br:28][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])=[C:8]([F:25])[CH:9]=2)=[CH:16][C:17]=1[O:23][CH3:24]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CO)c(OC)c2)cc1F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(OCc2ccc(CBr)c(OC)c2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of 3-[2-fluoro-4-(4-hydroxymethyl-3-methoxy-benzyloxy)-phenyl]-propionic acid ethyl ester (1.0 g, 2.76 mmol) in dichloromethane (25 mL) is added phosphorus tribromide (0.4 mL, 4.41 mmol) at 0° C. and the reaction mixture is stirred for 15 min at 0° C. The mixture is cooled to 0° C., diluted with water, and extracted with dichloromethane (2×100 mL). The combined extracts are washed with saturated brine, dried over Na2SO4, filtered, and concentrated to give the title compound (1.1 g, crude). 1H NMR (DMSO, 400 MHz) δ 7.34-7.32 (d, J=8 Hz, 1H), 7.12-7.08 (t, J=8 Hz, 1H), 6.96-6.94 (d, J=8 Hz, 2H), 6.67-6.64 (d, J=12 Hz, 2H), 4.98 (s, 2H), 4.55 (s, 2H), 4.12-4.09 (q, 2H), 2.90-2.88 (t, 2H), 2.60-2.56 (t, J=8 Hz, 2H), 1.25-1.22 (t, J=8 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][NH:31][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccc([N+](=O)[O-])cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(4-nitro-phenyl)-ethyl-amine to afford the title compound. MS: m/e=407 (M+H). 1H NMR (δ ppm): 11.72 (s, 1H); 8.87 (d, 1H, J=2.1 Hz); 8.78 (t, 1H, J=5.4 Hz); 8.68 (d, 1H, 2.1 Hz); 8.17 (d, 2H, J=8.6 Hz); 8.05 (t, 1H, J=2.1 Hz); 7.55 (d, 2H, J=8.6 Hz); 7.27 (s, 1H); 3.58 (m, 2H); 3.02 (t, 2H, J=7.1 Hz); 2.43 (q, 2H, J=7.4 Hz); 2.17 (s, 3H); 1.11 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:3]O.CN(C)C=O.S(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:20][CH2:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: CC(=Cc1ccc(C)cc1)CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C)cc1)CCl
Temperature: 13.5 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of 2-methyl-3-(4-methylphenyl)-2-propen-1-ol (750 g) in toluene (2367 ml) was added dimethylformamide (29.6 ml). To the solution was added dropwise thionyl chloride (431.1 ml) at 20° C. or below and the solution was stirred at 12 to 15° C. for 1.5 hr. Water was then added thereto under ice-cooling. The toluene layer was fractionated and a 10% aqueous solution of sodium carbonate was added thereto to adjust the pH to 5. The toluene layer was fractionated again, washed successively with 5% sodium hydrogencarbonate and 5% brine. The solvent was distilled off to give the title compound as an oil (776.8 g, yield 87.3%).
Reaction SMILES: O[C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]2[CH:6]([CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]2)[S:5][CH2:4][CH2:3]1.[OH-].[Na+]>C1C=CC=CC=1.ClCCl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH2:11]([N:8]1[CH2:9][CH:10]2[C:2]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:3][CH2:4][S:5][CH:6]2[CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC1(c2ccccc2)CCSC2CN(Cc3ccccc3)CC21
Agent: [Zr+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: c1ccc(CN2CC3SCCC(c4ccccc4)(c4ccccc4)C3C2)cc1
Yield: 85.8 %

Procedure:
43.7 g of zirconium tetrachloride are added to a solution of 12.2 g of (4RS,4aSR,7aRS)-4-hydroxy4-phenyl-6-benzylperhydrothiopyrano[2,3-c]pyrrole in 180 cm3 of benzene. The reaction mixture is refluxed for 1 hour and then brought to 20° C. and diluted with 200 cm3 of dichloromethane. 150 cm3 of a 4N aqueous solution of sodium hydroxide are added to the resulting cooled solution. The suspension obtained is filtered, the filtrate is decanted, the organic phase is washed with 200 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 5.2 cm, height 39 cm), eluting under a nitrogen pressure of 0.6 bar, with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions of 125 cm 3. Fractions 19 to 32 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 200 cm3 of diisopropyl oxide, the crystals are drained and dried. 6.2 g of (4aRS,7aRS)-6-benzyl-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of orange-colored crystals; melting point 130° C.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])[CH:15]=[CH:14]3)=[N:3][CH:2]=1.C=O.[C:35](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.[Cl-].[Na+].O.C(Cl)Cl>[F:32][C:29]([F:31])([F:30])[C:25]1[CH:24]=[C:23]([NH:22][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH2:9][N:8]([CH3:35])[CH2:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:21])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Temperature: 60 °C

Procedure:
5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (140 mg, 0.320 mmol) is suspended in 1,2-dichloroethane (5 mL), and formaldehyde (50 μl, 0.672 mmol) and acetic acid (36 μl, 0.629 mmol) and sodium triacetoxyborohydride (139 mg, 0.656 mmol) are added and the mixture heated to 60° C. overnight. The reaction is cooled to rt, diluted with water, brine and DCM. The organic phase is removed, dried, and concentrated to an oil that is purified via FCC (0-10% NH3/MeOH:DCM) to obtain 5-(6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.95 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (s, 1H), 8.56 (s, 1H), 8.27 (d, J=9.09 Hz, 1H), 8.09-8.13 (m, 2H), 7.96 (s, 1H), 7.65 (t, J=8.08 Hz, 1H), 7.48-7.51 (m, 2H,) 7.15 (dd, J=8.97, 2.40 Hz, 1H), 6.80 (d, J=3.79 Hz, 1H), 3.91 (s, 4H), 2.52 (s, 3H).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])(O)(O)=O.[K+]>CS(C)=O.C(OCC)(=O)C.[Cu]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of ethyl bromodifluoroacetate (1.1 equiv.) and 2-bromopyridine (1 equiv.) in DMSO was added copper bronze (2.2 equiv.) and the mixture was heated to 50° C. with stirring for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. A solution of potassium dihydrogen phosphate was added and the mixture stirred for 30 minutes before filtering. The copper salts were washed with ethyl acetate and the organic layer was washed with water. Solvent evaporation and purification by flash column chromatography on silica gel (diethyl ether-hexane) gave the title compound as a colorless oil in 82% yield.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[O:22]=[S:23]1(=[O:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:28][CH:25]3[CH2:26][CH2:27][S:23](=[O:29])(=[O:22])[CH2:24]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: NC1CCS(=O)(=O)C1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NC1CCS(=O)(=O)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 24.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), 1,1-dioxidotetrahydrothien-3-ylamine (10.4 mg, 0.077), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (5.1 mg, 24.3%). 1H NMR (400 MHz, CD3OD) δ 0.93 (dd, J=6.57, 1.26 Hz, 3 H) 1.05 (dd, J=6.32, 3.79 Hz, 3 H) 2.06-2.28 (m, 1 H) 2.40-2.59 (m, 2 H) 2.98 (td, J=12.57, 7.45 Hz, 1 H) 3.04-3.18 (m, 1 H) 3.21-3.29 (m, 1 H) 3.35-3.53 (m, 1 H) 4.51-4.66 (m, 1 H) 4.95-5.12 (m, 2 H) 5.40 (dd, J=19.20, 13.39 Hz, 1 H) 7.83-7.89 (m, 1 H) 8.17 (dd, J=3.28, 1.52 Hz, 1 H). [M+H] calc'd for C18H21FN4O4S, 409; found, 409.3.