Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](=[N:35][OH:36])[NH2:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]1[N:34]=[C:22]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH2:9]2)[O:36][N:35]=1
Reactant: NC(Cc1ccccc1Cl)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(Cc4ccccc4Cl)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 41 mg (0.22 mmol, 1.1 eq.) of 2-(2-chlorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 21 mg (22% of theory)
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Br:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([I:20])=[CH:13][CH:14]=3)[C:9](=[O:21])[C:8]=2[CH:7]=1>C1COCC1>[Br:5][C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([I:20])=[CH:13][CH:14]=3)[C:9]([CH:1]=[CH2:2])([OH:21])[C:8]=2[CH:7]=1
Reactant: C=C[Mg]Cl
Reactant: O=c1c2cc(Br)ccc2oc2ccc(I)cc12
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(Br)ccc2Oc2ccc(I)cc21
Temperature: -10 °C
Yield: 100 %

Procedure:
To a solution of vinylmagnesium chloride (6.86 mL, 10.97 mmol) at −78° C. under nitrogen atmosphere was added drop wise a solution of 2-bromo-7-iodo-9H-xanthen-9-one (2.00 g, 4.99 mmol) in THF (30 mL). The reaction mixture was allowed to slowly warm to −10° C., then the reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc followed by a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by filtration over silica gel (10% EtOAc/hexane) to give 2.14 g of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol as a white solid. Step 2: To a solution of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol (0.50 g, 1.16 mmol) and thiourea (0.18 g, 2.33 mmol) in acetic acid (2.00 mL) was added TFA (4.00 mL). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc, followed by a solvent mixture of CHCl3:i-PrOH (3:1). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (10%-100% EtOAc/hexane) to provide 0.36 g of 2′-bromo-7′-iodo-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.C1COCC1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1
Reactant: N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CO)CC1
Temperature: -78 °C

Procedure:
trans-[4-(8-chloro-1-iodoimidazo-[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (26.50 g, 67.66 mmol) was charged in a 400 mL steel bomb and was dissolved in 2M NH3 in isopropanol (300 mL) and anhydrous THF (10 mL). The reaction mixture was cooled to −78° C. Ammonia gas was bubbled vigorously into the solution for 8 min; then the bomb was tightly sealed and heated to 120° C. for 20 h. The crude reaction mixture was concentrated in vacuo, then the reaction residue was taken up with MeOH/CHCl3, loaded onto silica gel. The mixture was purified by a silica gel glass column chromatography [eluted with 1:1 CH2Cl2/EtOAc to 10%˜7 N NH3 in MeOH/CHCl3] to afford the desired product as a beige cream white solid; MS (ES+): m/z 373.01 (100) [MH+], 373.98 (50) [MH+2]; tR(polar-5 min/openlynx) 1.57 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])=[CH2:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cnc2c(N)nc3ccccc3c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 2-vinylbenzo[f][1,7]naphthyridin-5-amine (Example 29) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stiffed for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-ethylbenzo[f][1,7]naphthyridin-5-amine as a solid. 1H NMR (methanol-d4): δ 8.78-8.81 (m, 2H), 8.45 (d, 1H), 7.55-7.63 (m, 2H), 7.35-7.40 (m, 1H), 2.97 (q, 2H), 1.43 (t, 2H). LRMS [M+H]=224.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[S:18][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:20]([C:19]2[S:18][C:17]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:16][C:15]=2[CH3:14])=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)piperazine (3.72 g), 4-methyl-2-(4-pyridyl) -5-thiazolecarboxylic acid (4.4 g), triethylamine (2.5 g) and HOBt (2.7 g) in DMF (60 ml), was added WSC hydrochloride (4.217 g) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and to the residue were added dichloromethane and sodium bicarbonate aqueous solution. The organic layer was separated, washed with water and brine, dried and concentrated. The residue was purified with silica gel chromatography (dichloromethane:methanol=50:1) to give colorless crystals of the title compound (6.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:60][C:61]1[CH:70]=[CH:69][C:64]([C:65]([NH:67][CH3:68])=[O:66])=[CH:63][CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:60][C:61]3[CH:62]=[CH:63][C:64]([C:65](=[O:66])[NH:67][CH3:68])=[CH:69][CH:70]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Reactant: CNC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)cc1
Reaction time: 1 h
Yield: 28.4 %

Procedure:
3-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (58 mg, 148 μmol), HOBt (34.0 mg, 222 μmol) and EDCI (42.6 mg, 222 μmol) were combined with DMF (10 mL) to give a light yellow suspension. After 1 h, a clear yellow solution had been generated. DIPEA (47.9 mg, 64.7 μL, 370 μmol) and 4-amino-N-methylbenzamide (31.2 mg, 207 μmol) were added. After 15 h the mixture was concentrated in vacuo then diluted with water (10 mL) and filtered. The collected solid was washed with water (3×3 mL) and dried in vacuo. Purification by chromatography (silica, 50 g, Supelco VersaFlash, 0-5% methanol in dichloromethane, gradient over 15 min) gave a residue that was recrystallized from methanol to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (22 mg, 42.0 μmol, 28%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.60 (s, 1H) 9.98 (s, 1H) 8.62 (s, 1H) 8.53 (s, 1H) 8.36 (d, J=4.91 Hz, 1H) 8.16-8.27 (m, 2H) 8.10 (d, J=7.93 Hz, 1H) 7.87 (d, J=1.51 Hz, 4H) 7.61-7.76 (m, 2H) 7.42 (d, J=8.31 Hz, 1H) 7.13 (d, J=8.31 Hz, 1H) 4.03 (s, 3H) 3.77 (s, 3H) 2.79 (d, J=4.53 Hz, 3H); LC/MS: 524.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[ClH:20]>C(O)C.CCOCC>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][Cl:20])=[N:5][N:6]=1
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Reactant: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CCl)s1

Procedure:
1 g of 2-methyl-5-[2-(2,3-epoxypropoxy)-styryl]1,3,4-thiadiazole is left to stand in a mixture of 100 ml of ethanol and 5 ml of a 3 N solution of hydrogen chloride in ether for 12 hours. The precipitate formed is filtered off, washed neutral with ether and chromatographed on silica gel, using chloroform. Evaporation to dryness of the eluates containing the product gives spectroscopically pure 2-methyl-5-[2-(2-hydroxy-3-chloro-propoxy)-styryl]-1,3,4-thiadiazole of melting point 168°-170° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]4[CH:18]=[CH:19][N:20]=[C:13]4[C:12]=3[CH:21]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C[O:24]CCOC>>[N:20]1[CH:19]=[CH:18][N:14]2[C:13]=1[C:12]1[CH:21]=[C:8]([C:7]3[C:2](=[O:24])[NH:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=[CH:10][C:11]=1[O:17][CH2:16][CH2:15]2
Reactant: COCCOC
Reactant: Fc1ncccc1-c1ccc2c(c1)-c1nccn1CCO2
Agent: Cl
Product: O=c1[nH]cccc1-c1ccc2c(c1)-c1nccn1CCO2
Temperature: 80 °C

Procedure:
To a solution of 10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (100 mg, 0.4 mmol) in DME (4 mL) was added 10% aqueous HCl (4 mL). The reaction was allowed to stir and heated at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The crude was purified by Prep HPLC to provide 3-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)pyridin-2(1H)-one. LC/MS (ESI+): m/z 280 (M+H). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 8.71 (d, J=2.3, 1H), 7.72-7.50 (m, 1H), 7.47-7.21 (m, 1H), 7.15-6.86 (m, 2H), 6.29 (t, J=6.6, 1H), 4.44 (d, J=6.1, 4H).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[CH:25]1([C:28]2[C:29]([O:38][CH2:39][C:40]34[CH2:50][C:44]5([F:51])[CH2:45][C:46]([F:49])([CH2:48][C:42]([F:52])([CH2:43]5)[CH2:41]3)[CH2:47]4)=[CH:30][C:31]([F:37])=[C:32]([CH:36]=2)[C:33]([OH:35])=O)[CH2:27][CH2:26]1.CS(N)(=O)=O.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1>>[CH:25]1([C:28]2[C:29]([O:38][CH2:39][C:40]34[CH2:50][C:44]5([F:51])[CH2:43][C:42]([F:52])([CH2:48][C:46]([F:49])([CH2:45]5)[CH2:47]3)[CH2:41]4)=[CH:30][C:31]([F:37])=[C:32]([CH:36]=2)[C:33]([NH:64][S:61]([CH:58]2[CH2:60][CH2:59]2)(=[O:63])=[O:62])=[O:35])[CH2:26][CH2:27]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Yield: 79 %

Procedure:
Following the procedure as described in Example 150 step 5 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid and to replace methyl sulfonamide with cyclopropanesulfonamide. Purification by silica gel column chromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.10 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (br s, 1H), 7.12 (d, J=8.33 Hz, 1H), 6.94 (d, J=12.86 Hz, 1H), 3.93 (s, 2H), 3.09-2.99 (m, 1H), 2.25-2.13 (m, 3H), 2.10-1.98 (m, 4H), 1.85-1.75 (m, 6H), 1.12-1.01 (m, 4H), 0.93-0.84 (m, 2H), 0.66-0.59 (m, 2H); MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.O.[Cl-].[Na+].O>[C:16]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Yield: 89.8 %

Procedure:
To a solution of N-Boc-piperazine (14) (1.00 g, 5.37 mmol) in dioxane (5 mL), a solution of NaOH (0.50 g, 12.9 mmol) in water (5 mL) followed by a solution of benzoyl chloride (0.75 mL, 6.44 mmol) in dioxane (2 mL) under vigorous stirring were added. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with brine (20 mL), and extracted with ethyl acetate (2×25 mL). The organic extract was washed successively with brine (20 mL), saturated NaHCO3 (20 mL), saturated KH2PO4 (20 mL), and dried (Na2SO4). The solvents were evaporated to give the title compound (1.400 g, 90%) which was used in the next step of the synthesis without further purification. 1H NMR (CDCl3, HMDS), δ: 1.41 (s, 9H), 2.86 (t, J=5.0 Hz, 4H); 3.62 (t, J=5.0 Hz, 4H); 7.34 (s, 5H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:19])[C:12](=[O:20])[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:10]2)=[CH:4][CH:3]=1.[Cl-].[CH3:27][Zn+].O>O1CCCC1.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>[Cl:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([CH3:27])=[CH:3][CH:4]=1)[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2=[O:20]
Reactant: C[Zn+]
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2c(Cl)cccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(C)nc2)c2c(Cl)cccc2c1=O
Reaction time: 0.25 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-8-chloro-4-oxo-1,4-dihydrocinnoline-3-carboxylate [(Example 69, Step 1), 0.11 g, 0.25 mmol] was dissolved in tetrahydrofuran (1.5 mL), sparged under nitrogen and treated with methylzinc chloride (0.18 mL, 2.0 M tetrahydrofuran solution, 0.35 mmol, 1.4 equiv) and 1,1′bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.013 mmol, 0.05 equiv). After stirring for 15 minutes, tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol, 0.2 equiv) were added and the mixture was stirred at ambient temperature for an additional 2 hours. The mixture was poured into water, extracted twice with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([CH:32]=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:34]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([C:32]([OH:36])=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:34]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C=O)ccc23)ccc1OC(C)C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C(=O)O)ccc23)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a solution of 7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (130 mg, 0.27 mmol) in acetone (1.5 mL) was added a solution of potassium permanganate (43 mg, 16 μL, 0.27 mmol) in water (1.5 mL) and acetone (1.5 mL) dropwise at 0° C. The mixture was allowed to stir at room temperature for 2 h before it was concentrated onto Celite from methanol. Column chromatography on the residue (0-20% EtOAc/CH2Cl2) gave 7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxylic acid (13%).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([C:13]3[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[CH2:31]([O:19][C:16]1[CH:15]=[N:14][C:13]([CH:9]2[C:10](=[O:12])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:18][CH:17]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(=O)C(c1ncc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2=O)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[N:30]=[C:31]=S.CI>CO>[CH3:1][N:2]([CH3:21])[C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]([CH3:19])[C:31]([NH:30][C:24]4[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=4[F:29])=[N:20][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNc1ccc(Oc2ccnc(C(=O)N(C)C)c2)cc1N
Reactant: Fc1cccc(F)c1N=C=S
Solvent: CI
Solvent: CO
Product: CN(C)C(=O)c1cc(Oc2ccc3c(c2)nc(Nc2c(F)cccc2F)n3C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid dimethylamide (1 eq) in methanol was treated with 2,6-difluorophenylisothiocyanate (1 eq) and stirred overnight. To the reaction mixture, methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, and the residue purified by reverse phase HPLC. HPLC, 1.66 min; MS: MH+=424.1
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:14][C:13]=1[F:26])([CH3:11])[CH3:10])=O)(C)(C)C.[NH2:27][C:28]1[CH:36]=[CH:35][C:31]([CH2:32][CH2:33][OH:34])=[CH:30][CH:29]=1>>[NH2:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([CH2:32][CH2:33][OH:34])=[CH:30][CH:29]=3)[N:19]=2)=[CH:14][C:13]=1[F:26])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1F
Reactant: Nc1ccc(CCO)cc1
Product: CC(C)(N)c1ccc(-c2nc(Nc3ccc(CCO)cc3)ncc2Cl)cc1F

Procedure:
The title compound was prepared from 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)-3-fluorophenyl]-2,5-dichloropyrimidine (1.60 g, 4.0 mmol) and 4-aminophenethyl alcohol (826 mg, 6.0 mmol) following the method of Example 1.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1cc(F)ccc1F
Yield: 66 %

Procedure:
Prepared in 66% yield from 2-chloronicotinonitrile and 2,5-difluorophenylboronic acid according to the procedure described for Example 153A. 1H NMR (CDCl3) δ 7.19-7.23 (m, 2H), 7.29-7.34 (m, 1H), 7.48 (dd, J=8.0, 4.9 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 8.92 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=1.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(OCC)C>[CH3:12][N:10]1[CH:11]=[C:7]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=[N:9]1
Reactant: Cn1cc(Br)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1

Procedure:
To a precooled (<−10° C. internal temperature) solution of 1.6M n-butyl lithium in hexanes (100 ml) in anhydrous diethyl ether (100 ml) under argon was added a solution of 4-bromo-1-methyl-1H-pyrazole (23.42 g) from Example 111 in diethyl ether (50 ml) at a rate to maintain the temperature. The reaction was allowed to stir for a further 20 minutes before tributyltin chloride (43.4 ml) was added in diethyl ether (50 ml). The reaction temperature was allowed to rise to 20° C. The reaction was diluted with diethyl ether and the insoluble material removed by suction filtration. Evaporation of the solvent in vacuo afforded 56 g of the title compound as an oil. MS, m/z: 373 [M+H]+. Residual amounts of tin residues were removed from the oil by distillation using a kugelrohr apparatus under high vacuum at 170° C.
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.[NH2:34][C@@H:35]([CH3:42])[CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40].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:34]4[C@@H:35]([CH3:42])[CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CC(C)NCC[C@H](C)N
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 56.3 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (27 mg, 0.060 mmol) and free based [(3S)-3-aminobutyl](1-methylethyl)amine (67 mg, 0.51 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (18 mg, 56%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (15 mg, >1.00%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.54-1.58 (m, 1H), 1.94-2.03 (m, 1H), 2.71-2.76 (m, 1H), 2.82-2.88 (m, 1H), 3.13-3.16 (m, 1H), 4.16-4.19 (m, 1H), 4.30-4.33 (m, 1H), 4.48 (m, 1H), 4.55-4.65 (m, 2H), 4.97-5.00 (m, 1H), 6.97-7.01 (m, 2H), 7.30-7.34 (m, 2H), 8.28 (s, 1H), 10.51 (m, 1H), 12.55 (s, 1H); ES+ MS: 443 (M+1).