Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>C(Cl)Cl>[Cl:17][C:16]1[CH:15]=[CH:14][C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:3][C:2]=1[N:1]=[C:18]=[S:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl 3-amino-4-chlorobenzylcarbamate (2.57 g, 10.0 mmol) was added to a mixture of 1,1′-thiocarbonyldi-2-pyridone (2.55 g, 11.0 mmol) and DCM (90 mL) and it was stirred at rt for 4 h. The mixture was diluted with DCM and filtered over silica gel. The organic layer was concentrated to give the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:3][C:2]=1[NH:1][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-methoxyphenyl)piperazin-1-yl) (phenyl)methanone (2 g, 6.4 mmol) and phenylboronic acid (2.34 g, 19.2 mmol) in DCM (100 mL) was added triethylamine (2.7 mL, 19.2 mmol) and Cu(OAc)2 (1.74 g, 9.6 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-methoxy-3-(phenylamino) phenyl)piperazin-1-yl)(phenyl)methanone (2.0 g), 80% yield. 1H NMR (500 MHz, CDCl3): δ 3.0 (bs, 2H), 3.15 (bs, 2H), 3.59 (bs, 2H), 3.89 (s, 3H), 3.95 (bs, 2H), 6.18 (s, 1H), 6.46 (dd, J=2.5, 3 Hz 1H), 6.85 (d, J=9 Hz, 1H), 7.01 (m, 2H), 7.19 (d, J=7.5 Hz, 2H), 7.34 (m, 2H), 7.49 (m, 5H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]>>[CH2:20]([S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCS(=O)(=O)c1ccc(C=O)cc1
Product: CCS(=O)(=O)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-ethylsulfonylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-ethylsulfonylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=2[CH2:3]1.[C:21]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl>[C:21]([N:26]1[CH2:31][CH2:30][N:29]([CH:2]2[C:8]3[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:4]=3[CH2:3]2)[CH2:28][CH2:27]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(Cl)C2
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3ccc(OC)cc3Sc3ccc(SC)cc32)CC1
Temperature: 0 °C

Procedure:
24 G. of 10-chloro-10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin in 100 ml. of chloroform are heated with 55 ml. of 1-carbethoxypiperazine under reflux conditions for 20 hours. The mixture is poured on to ice/water and extracted with chloroform. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained crude 1-carbethoxy-4-(10,11-dihydro-3-methoxy-8-methylthiodibenzo[b,f]thiepin-10-yl)-piperazine.
Reaction SMILES: [Cl:1]C1C(N(C)S(C)(=O)=O)=NC([NH:18][C@H:19]([C:21]2[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH3:20])=NC=1NC1C=C(OC(C)C)NN=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[F:27][C:24]1[CH:23]=[N:22][C:21]([C@@H:19]([NH2:18])[CH3:20])=[N:26][CH:25]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(C)(=O)=O)c2Cl)n[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tert-butyl-1-(5-fluoropyrimidin-2-yl)ethylcarbamate (Method 10, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed give the title compound as white solid (quantitative). MS: Calcd.: 141. Found: [M+H]+ 142.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[O:40]=[C:41]1[CH2:45][CH2:44][CH2:43][N:42]1[CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:48][CH2:47][CH:46]([N:42]4[CH2:43][CH2:44][CH2:45][C:41]4=[O:40])[CH2:51][CH2:50]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: O=C1CCCN1C1CCNCC1
Product: Cc1ccccc1-c1nc(N2CCC(N3CCCC3=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 96.8 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (30.3 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine (96.0 mg, 97%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:32])[N:13]2[C:16](=[C:25](OS(C)(=O)=O)[CH3:26])[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C1C=CC=CC=1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:32])[N:13]2[C:16](=[C:25]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH3:26])[C:17]([O:19][CH2:20][C:21]([Cl:23])([Cl:22])[Cl:24])=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2,2,2-trichloroethyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.52 g) in benzene (30 ml) is added morpholine (0.48 ml) at beneath 10° C. After stirring for 1 hour, the mixture is washed with water, dried, and evaporated. Purification of the obtained residue by chromatography over silica gel gives 2,2,2-trichloroethyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate (0.76 g). Yield: 50%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)nc1
Product: N#Cc1cc(-c2ccc(F)nc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (68 mg, 89%), MS (ISP) m/z=307.4 [(M+H)+], mp 268° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34].O>O1CCOCC1.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>[CH3:32][S:33]([C:36]1[CH:41]=[C:40]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: FC(F)(F)Oc1ccc(Nc2cc(N3CCOCC3)cc(Cl)n2)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
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: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCOCC3)cc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Yield: 30 %

Procedure:
To a solution of (6-chloro-4-morpholin-4-yl-pyridin-2-yl)-(4-trifluoromethoxy-phenyl)-amine (75 mg, 0.20 mmol) in 1,4-dioxane (8 mL) were added 2N sodium carbonate solution (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.010 mmol), followed by 3-methanesulfonyl phenyl boronic acid (48 mg, 0.24 mmol). The resulting reaction mixture was refluxed for 8 hours, after which time water was added (100 mL) to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified by column chromatography using 230-400 mesh silica gel (elution 2:98 methanol:DCM) to afford the desired compound pale yellow solid (30 mg, yield 30%.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1>C(O)(=O)C.O>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[NH:16][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: NNc1ccc(Br)cc1
Reactant: O=CCCCCCl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: ClCCCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 24.5 %

Procedure:
5-Chloropentanal (ca. 70% pure, 8.0 g) was added to a suspension of 4-bromophenylhydrazine hydrochloride (13.4 g) in aqueous acetic acid (50%, 300 ml). The mixture was heated rapidly to boiling with vigorous stirring and maintained at reflux for 7 hours. The resulting dark brown solution was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (4×150 ml). The combined extracts were washed with water (200 ml) and saturated aqueous sodium hydrogen carbonate (4×250 ml), dried (MgSO4), filtered and evaporated to a dark brown oil (14.7 g), which was purified on a silica column (Kieselgel 60, 200 g) eluted with ethyl acetate:light petroleum (b.p. 60°-80°) (1:2) followed by bulb to bulb distillation twice in vacuo to give the title compound as a yellow oil (4 g) b.p. 200° C., 0.5 mm, which rapidly darkened on storage.
Reaction SMILES: [NH2:1][C:2]([CH2:11][OH:12])=[CH:3][C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:13][C:14]1[C:15]([NH:20]N)=[N:16][CH:17]=[CH:18][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:13][C:14]1[C:15]([N:20]2[C:4]([OH:10])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][C:2]([CH2:11][OH:12])=[N:1]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(=O)C=C(N)CO
Reactant: NNc1ncccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl

Procedure:
A mixture of ethyl 4-amino-5-hydroxy-2-oxopent-3-enoate (2.5 g, 14 mmol), 3-chloropyridin-2-ylhydrazine (2.07 g, 14 mmol) and p-toluenesulphonic acid monohydrate (2.5 g, 13 mmol) was stirred in 25 ml of acetonitrile at 25° C. for 5 hours. The precipitate was isolated by filtration and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography on SiO2 (eluent: hexane/ethyl acetate). Oil. Yield 4.2 g (90%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][O:7][N:6]=1)N.N([O-])=O.[Na+].[ClH:20]>O>[OH:1][N:2]=[C:3]([Cl:20])[C:5]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][O:7][N:6]=1
Reactant: Cl
Reactant: NC(=NO)c1nonc1N1CCOCC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: ON=C(Cl)c1nonc1N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of N′-hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidamide (66 mg, 0.3 mmol) in 6.0 M HCl (0.62 mL) at 5-10° C. was treated with a solution of sodium nitrite (32 mg, 0.47 mmol) in water (0.5 mL) dropwise and stirred for 2 h at 0° C. The suspension was filtered and the solid washed with ice water to give desired product (22 mg, 30%). The filtrate was extracted with ethyl acetate (30 mL) which was washed with brine (10 mL), filtered and concentrated to give additional product (23 mg, 32%) that contained minor impurities. The combined material was used immediately in the next step.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Br.[K+].[Br-]>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: Br
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc2c1

Procedure:
Into a 1000 mL three-necked round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet, and a condenser, 2,3-bis(4-methoxyphenyl)-quinoxaline-6-carboxylic acid (34.7 g, 89.8 mmol) was dissolved in acetic acid (260 mL). Hydrobromic acid (500 mL) was then added to the clear, yellow mixture at room temperature. The reaction mixture was heated under reflux with vigorous stirring until the solution become homogeneous. After the red-brown mixture had been allowed to cool down on its own, it was poured into distilled water. The resulting light brown precipitate was collected by suction filtration and dried under the reduced pressure to give 31.9 g (99% crude yield) of yellow solid: mp 319-320° C. (dec.). Anal. Calcd. for C21H14N2O4: C, 70.38%; H, 3.94%; N, 7.82%. Found: C, 66.70%; H, 3.98%; N, 7.20%. FT-IR (KBr, cm−1): 1698, 3396. Mass spectrum (m/e): 358 (M+, 100% relative abundance). 1H-NMR (DMSO-d6, ppm) δ6.76-6.79 (d, 4H, Ar), 7.36-7.40 (dd, 4H, Ar), 8.09-8.12 (d, 1H, Ar), 8.21-8.25 (dd, 1H, Ar), 8.57 (d, 1H, Ar). 13C-NMR (DMSO-d6, δ in ppm): 114.93, 128.84, 129.21, 130.34, 131.11, 131.52, 139.32, 142.03, 153.75, 154.35, 158.44, 166.68.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Br:10])N.N([O-])=[O:12].[Na+]>O.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:7]=[CH:8][C:9]=1[Br:10]
Reactant: O=N[O-]
Reactant: COc1cc(N)ccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(O)ccc1Br
Reaction time: 3 h
Yield: 69.9 %

Procedure:
3-Methoxy-4-bromoaniline (D1) (10.0 g, 49 mmoles) in water (60 ml) and concentrated sulphuric acid (30 ml) was treated with a solution of sodium nitrite (3.4 g, 49 mmoles) in water (15 ml) dropwise keeping the temperature below 5° C. The resulting slurry was then added slowly to a mixture of water (60 ml) and concentrated sulphuric acid (30 ml) at 80° C. and stirred at this temperature for 3 hrs. The mixture was cooled and extracted with dichloromethane (2×200 ml). The organics were then extracted with 2N sodium hydroxide solutions (2×100 ml). The aqueous was washed with more dichloromethane (2×200 ml) then acidified to pH 1. Extraction with dichloromethane, drying (Na2SO4) and evaporation to dryness gave the title compound (D8) (6.95 g, 69%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[NH:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1NCC(F)(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1NCC(F)(F)F
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (210 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.57 mmol, Intermediate-62, single enantiomer) and phenyl formate (140 mg, 1.1 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[O:18]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:28]1[CH:29]=[CH:30][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][CH:27]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2oc1=O
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1c(O)c2cc(-c3ccc(Oc4ccccc4)cc3)ccc2oc1=O

Procedure:
4-Hydroxy-2-oxo-6-(4-phenoxy-phenyl)-2H-chromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester and 4-phenoxyphenylboronic acid under conditions analogous to example 3-a. MS ESI(+) m/e: 389 (M+1).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1ccc(Cc2cc3ccccc3s2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1

Procedure:
2-(4-Ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (5.4 mmoles, 0.42 ml), sulfuryl chloride (4.6 mmoles, 0.37 ml) and 2-(4ethylbenzyl)benzo[b]thiophene (2.7 mmoles, 0.69 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.43 g (45%) of an orange solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].CCOCC>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:1][N:2]=[C:3]([NH2:7])[CH:4]([OH:6])[CH3:5])=[O:13]
Reactant: CC(O)C(N)=NO
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)C(N)=NOC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.45 g crude N′,2-dihydroxypropanimidamide was cooled on an ice-bath with 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g 3-chlorobenzoyl chloride was added. The mixture was warmed to r.t. and stirred for 2 h. Addition of Et2O (200 mL), washing with sat. aq. NH4Cl and re-extraction of the aq. layer gave after combining and concentration of the org. layers followed by drying in vacuo 27.24 g of crude title compound, which was used directly in the next step for 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol. LC-MS (M++1): 243
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH2:16][CH2:17][N:18]([CH2:26][CH2:27]Cl)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:11]([O:13][CH3:14])=[O:12])[CH2:27][CH2:26][N:18]([C:19]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:25])[CH2:17][CH2:16]1
Reactant: COC(=O)Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 17 %

Procedure:
A flask was charged with sodium hydride (2.14 g, 89.2 mmol) and dimethylformamide (70 ml) at 0° C. under nitrogen. Methyl 2-(2-fluorophenyl)acetate (5 g, 29.7 mmol) was added to the flask, and after stirring for 25 min, tert-butyl bis(2-chloroethyl)carbamate (8.6 g, 35.6 mmol) was added. The reaction was allowed to warm to rt and stirred overnight. The reaction was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (5×100 mL). The organics were collected, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified via silica gel chromatography (10/90→50/50 ethyl acetate/hexanes) to yield 1.7 g (17%) of the desired product. 1H-NMR (CDCl3, 400 MHz) δ ppm 7.29 (m, 1H), 7.24 (m, 1H), 7.12 (m, 1H), 7.00 (m, 1H), 3.86 (m, 2H), 3.67 (m, 3H), 3.22 (m, 2H), 2.37 (m, 2H), 1.96 (m, 2H), 1.44 (s, 9H). Mass spec.: 360.22 (MNa)+. LC tr=3.503 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=4 min, Flow rate=4 mL/min)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH3:12])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)ccc1N
Yield: 96.1 %

Procedure:
5-Chloroanthranilic acid (15.0 g), (CH3)2SO4 (11.6 g) and K2CO3 (12.7 g) were refluxed in acetone (150 g) for 30 minutes. The mixture was concentrated to about 90 g, and thereto was added water (90 g). The mixture was extracted with toluene (75 g), and the organic layer was concentrated to give methyl 5-chloroanthranilate (15.6 g, 96%).