Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[N:20]2[N:19]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C.C(O)(C)(C)C>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[N:20]2[C:21]([CH:22]=[N:23][C:18]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:13][N:12]=3)=[N:19]2)=[CH:24][CH:25]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nn12
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (0.154 g, 0.804 mmol), 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.105 g, 0.365 mmol), Cesium fluoride (0.139 g, 0.914 mmol), N,N-Diisopropylethylamine (0.1400 mL, 0.8039 mmol) and tert-Butyl alcohol (2.00 mL, 20.9 mmol) were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-amine as a yellow solid (30 mg, 22%). LCMS (E/I+) 416.18 (M+H). NMR 1H (DMSO-d6)-9.80 (s, 1H), 9.72 (bs, 1H), 9.01 (s, 1H), 7.99 (s, 1H), 7.90 (d, 1H, J=9.58 Hz), 7.80 (d, 1H, J=7.49), 7.53 (d, 1H, J=9.38 Hz), 7.47 (d, 1H, J=7.59 Hz), 7.24 (d, 1H, J=8.04 Hz), 7.14 (t, 1H, J=7.15 Hz), 7.01 (s, 2H), 3.80 (bs, 5H), 3.55 (d, 2H, J=11.72 Hz), 3.19 (q, 2H, J=10.34 Hz), 2.96 (t, 2H, J=11.72 Hz), 2.83 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH3:21])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-methylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([Br:29])=[CH:23][C:22]=2[O:21]1.C(=O)(O)[O-].[Na+]>C1CCCCC1.CCCCCCC.O>[C:5]12([C:26]3[CH:25]=[C:24]([Br:29])[CH:23]=[C:22]4[O:21][CH2:20][O:28][C:27]=34)[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Solvent: CCCCCCC
Product: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.82 g (24.9 mmol) of acetoxyadamantane and 0.75 ml (139 mmol) of concentrated sulphuric acid are added to 5 g (24.9 mmol) of 3,4-methylenedioxybromobenzene in 35 ml of cyclohexane and 35 ml of heptane. The reaction medium is stirred at room temperature overnight. This medium is then hydrolyzed with 250 ml of water, neutralized with sodium bicarbonate, extracted with 200 ml of dichloromethane, dried over magnesium sulphate and evaporated, to give 2.89 g (34.8%) of the expected derivative which melts at 134° C.)
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18](Cl)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[O:1]1[C:5]([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][N:11]3[C:27](=[O:28])[N:14]4[N:15]=[CH:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)=[C:18]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:13]4=[N:12]3)=[CH:8][CH:7]=2)=[CH:4][CH:3]=[N:2]1
Reactant: OB(O)c1ccccc1
Reactant: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
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: Cc1ccccc1
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccccc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Yield: 14 %

Procedure:
To a stirred solution of 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.23 mmol), prepared as described in Example 355 in toluene (2 mL) in a round bottomed flask was added Pd(PPh3)4 (16 mg, 0.014 mmol) under bubbling argon. Phenyl boronic acid (36 mg, 0.3 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (97 mg, 0.91 mmol) pre-dissolved in water (0.25 mL) was added to the suspension. Argon was bubbled through this suspension for 10 min before the flask was placed in an oil bath preheated at 120° C. The reaction was stirred at reflux for 6 days. The reaction was then allowed to cool to RT. After this time, the reaction mixture was poured into water (10 mL). The resultant solution was extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL) followed by saturated aqueous NaCl (2×5 mL). The organic layer was dried (MgSO4), filtered and concentrated to obtain crude product. This crude product was purified by reverse phase HPLC to give the title compound, 2-(4-(isoxazol-5-yl)benzyl)-7-(4-chlorophenyl)-8-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (15.5 mg, 14%) as pale yellow solid. HPLC: 3.68 min; MS, M+H=480; 1H NMR (CDCl3), ppm: 8.31 (1H, d, J=2.0 Hz), 8.22 (1H, s), 7.77 (2H, d, J=10.0 Hz), 7.51 (2H, d, J=10.0 Hz), 7.26-7.42 (7H, m), 7.09 (2H, d, J=10.0 Hz), 6.54 (1H, d, J=5.0 Hz), 5.29 (2H, s).
Reaction SMILES: NC(N)=O.[CH3:5][S:6][CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=1[OH:22])(=[O:13])=[O:12].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([S:11]([NH:10][CH2:9][CH2:8][CH2:7][S:6][CH3:5])(=[O:13])=[O:12])[C:15]=1[OH:22])=[O:32]
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Br
Agent: NC(N)=O
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 73.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-(3-methylthiopropyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (250 mg, 0.80 mmol) and 2-bromophenylisocyanate (191 mg, 0.97 mmol) were coupled to form the desired urea (300 mg, 74%). 1H NMR (MeOD-d4): δ 8.28 (d, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H), 7.05 (d, 1H), 7.00 (t, 1H), 3.08 (t, 2H), 2.48 (t, 2H), 1.98 (s, 3H), 1.74 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1([CH3:21])[CH2:16][C:15]2[C:10](=[C:11]([Cl:19])[C:12]([Cl:18])=[C:13]([OH:17])[CH:14]=2)[CH:9]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Na+]>CN(C)C=O>[OH:20][CH:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][CH2:29][C:30]([OH:32])=[O:31])=[C:12]([Cl:18])[C:11]=2[Cl:19])[CH2:16][C:8]1([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: CC1(Cc2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cc2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1O

Procedure:
(1-Hydroxy-2-benzyl-2methyl-6,7-dichloro-5-indanyloxy)acetic acid is prepared following subtantially the same procedure described in Example 4, Step F, using the following substances: 2-benzyl-2-methyl-6,7-dichloro-1,5indandiol (4.8 g., 0.015 mole); potassium carbonate (3.6 g.); ethyl bromoacetate (3.1 ml.); and dimethylformamide (35 ml.), and hydrolyzing the resultant ester with aqueous sodium hydroxide in accordance with Example 4, Step F, gives (1-hydroxy-2-benzyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:14]([Cl:13])(=[O:16])=[O:15])[C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
12.3 g (0.075 mole) of 4-(1,1-dimethylethyl)anisole, dissolved in 30 ml of methylene chloride, are added dropwise, while cooling with ice, to 16.5 ml of chlorosulfonic acid, dissolved in 20 ml of methylene chloride. The mixture is stirred for 40 minutes and is then poured into ice water. The organic phase is separated off, washed with water, dried with MgSO4 and concentrated.
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([CH:33]=[N:34][N:35]=2)[C:7](SC)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:30])(=[O:3])[NH2:2].[Br-].[Cl:37][C:38]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:39]=1[CH2:40][Zn+].O1CCCC1>ClCCl.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]([C:4]1[C:5]2[N:6]([CH:33]=[N:34][N:35]=2)[C:7]([CH2:40][C:39]2[C:38]([Cl:37])=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:46])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:30])(=[O:3])[NH2:2]
Reactant: CSc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)c(C(N)=O)c2nncn12
Reactant: Clc1cccc(Cl)c1C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)n4cnnc4c3C(N)=O)c(F)c2)CC1
Temperature: 70 °C

Procedure:
To a mixture of the product of Example 28E (200 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol) was added 0.5M 2,6-dichlorobenzylzinc bromide in tetrahydrofuran (4 mL, 2 mmol) under nitrogen atmosphere and the mixture was heated at 70° C. for 16 hours. After cooling to ambient temperature, the mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×20 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 97/3 dichloromethane/methanol to give the title compound. MS: 615 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[S:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S[CH2:41]CC(OC)=O>C(Cl)Cl.[Zn+2].[I-].[I-]>[CH3:41][O:15][C:14](=[O:16])[CH2:13][CH2:12][S:11][CH:10]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Reactant: COC(=O)CCS
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)CCSC(CCCc1ccccc1)c1ccc(OCCCOc2ccc(C(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of the product of Step 4 (270 mg) and methyl 3-mercaptopropionate (250 mL) in 20 mL of CH2Cl2 was added ZnI2 (700 mg) at 0° C. The mixture was stirred for 20 min. at r.t. and then quenched with 20 mL of 25% NH4OAc, extracted with 100 mL of 2:1 Hexane/EtOAc. The organic extract was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluted with 5:1 Hexane/EtOAc to give 320 mg of the title compound.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:9]([O:11][C:12](=[O:13])[CH:2]21)=O.[NH2:14][CH2:15][C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].Cl>O>[C:16]([CH2:15][N:14]1[C:12](=[O:13])[CH:2]2[CH:3]([CH:4]3[CH2:7][CH2:8][CH:1]2[CH:6]=[CH:5]3)[C:9]1=[O:11])([OH:18])=[O:17]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CN1C(=O)C2C3C=CC(CC3)C2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
To a suspension of bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (688 mg, 3.9 mmol) in H2O (10 mL) was added glycine (348 mg, 4.6 mmol), and a solution of K2CO3 (321 mg, 2.3 mmol) in H2O (2 mL). The mixture was heated to reflux temperature and allowed to react for 4 hrs. After cooling to room temperature, the mixture was acidified with conc. HCl until the pH reached 1 and extracted with ethyl acetate (EtOAc). The organic layer was washed with brine and dried over Na2SO4. Removal of the solvent gave a colorless solid which was recrystallized from EtOAc/hexane to yield the product as colorless crystals: 653 mg (72% yield), mp=142° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(-c2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccccn2)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.15 g), 2-(3-aminophenyl)pyridine (1.12 g) and potassium carbonate (1.36 g) in diglyme (15 ml) was stirred at 150° C. for 3 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 1:1) to give 3-nitro-2-[3-(2-pyridyl)phenylamino]pyridine (1.68 g)
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[Br:13][C:14]1[C:15](Cl)=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Br:13][C:14]1[C:15]([NH:1][C:2]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Br
Yield: 28.5 %

Procedure:
A solution of 2-amino-3-fluoro-N-methyl-benzamide (625 mg, 3.72 mmol), 5-bromo-2,4-dichloro-pyrimidine (1025 mg, 4.498 mmol), and N,N-diisopropylethylamine (1250 uL, 7.18 mmol) in N-methylpyrrolidinone (10.0 mL) was heated at 100° C. overnight. Solvent was removed by rotary evaporation and the residue was triturated with DCM to afford 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a yellow solid (381 mg, 28%) that had the following properties: 1H-NMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 8.61 (m, 1H), 8.51 (s, 1H), 7.51-7.44 (m, 3H), 2.73 (d, J=4.4, 3H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]C(C)(C)C.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[C:18]1=[O:19])[CH3:13].[NH4+].[Cl-]>C1COCC1>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20]([OH:21])([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[C:18]1=[O:19])[CH3:30]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Brc1ccsc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccsc2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To 3-bromothiophene (105.5 mg, 2.1 eq) in anhydrous THF (2 mL) under a nitrogen atmosphere and with stirring was added t-BuLi (0.38 mL, 2.1 eq, 1.7 M in pentane) at −40° C. (bath temperature). Stirring was continued for 30 minutes after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added dropwise. The resulting red colored solution was stirred at −40° C. for 8 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1% to 2% MeOH in CHCl3) to give the title compound as a light brown foam (124.5 mg, 99%).
Reaction SMILES: [F:1][C:2]1([CH2:12][OH:13])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:11][O:10][CH2:9]2)[CH2:4][CH2:3]1.[H-].[Na+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17]>O1CCCC1>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:13][CH2:12][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH:8]2[CH2:9][O:10][CH2:11]2)[CH2:6][CH2:7]1)#[N:17]
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Reactant: OCC1(F)CCN(C2COC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(S(N)(=O)=O)ccc1OCC1(F)CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 517B (0.185 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.090 g). After 30 minutes, 3-cyano-4-fluorobenzenesulfonamide (0.178 g) was added in one portion. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with 1N aqueous HCl (4 mL), diluted with dichloromethane (30 mL) and saturated aqueous NaHCO3 (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting solid material was triturated with dichloromethane and filtered to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][NH2:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C#N)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(CN)ccc1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 5-chloro-6-methylpicolinonitrile (3) (200 mg, 1.31 mmol) in MeOH (10 mL) was added NaBH4 (150 mg, 3.94 mmol), CoCl2 (5 mg) at room temperature. After 30 min, the mixture was filtered and purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% MeOH in water with 10 mmol NH4HCO3 modifier) to afford the compound as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(CCC2(O)CCCCC2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)O)c2)cc1)c1ccc(CCC2(O)CCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.12 mL, 0.23 mmol) was added to a solution of {5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 149-(1); 19.9 mg, 0.038 mmol) in methanol (0.4 mL), and the mixture was stirred at room temperature for two hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (dichloromethane:methanol=9:1) to give the title compound (12.5 mg, 64%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH:30]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[N:35]=1)([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.O>[CH:30]([O:33][C:34]1[N:35]=[C:36]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[S:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[N:14][N:15]=4)[CH:9]=3)[N:4]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:21])=[O:22])[CH:3]=2)[CH:37]=[CH:38][CH:39]=1)([CH3:32])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Reactant: CC(C)Oc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 29.3 %

Procedure:
A yellow suspension of 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (300 mg, 0.536 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CombiPhos Catalysts, Inc., Princeton, N.J.; 198 mg, 0.751 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (Aldrich; 18.99 mg, 0.027 mmol), and potassium phosphate (341 mg, 1.609 mmol) in a mixture of IPA (3.5 mL) and H2O (1.50 mL) was stirred at 100° C. for 10 min. The mixture was partitioned between EtOAc (80 mL) and H2O (50 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-60% EtOAc/Hex) furnished 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (89.3 mg, 0.157 mmol, 29%) as a colorless oil. MS (ESI, pos. ion) m/z: 569.1 (M+1).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:5])=[O:4].Cl[CH2:20][C:21]1[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:28][O:27][C:22]1[C:21]([CH2:20][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][CH2:11][C:7]3[S:8][CH:9]=[CH:10][C:6]=3[S:3]([CH3:2])(=[O:4])=[O:5])[CH2:14][CH2:15]2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CS(=O)(=O)c1ccsc1CCC1CCNCC1
Reactant: COc1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(CCc2sccc2S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
4.41 g of 4-[2-(3-methylsulfonyl-2-thienyl)ethyl]piperidine hydrochloride, 2.36 g of 3-(chloromethyl)-2-methoxypyridine and 5.90 g of potassium carbonate were suspended in 30 ml of N,N-dimethylformamide, and the mixture was stirred for 12 hours at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 809 mg of the title compound as a colorless oil (quantitatively).