Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:27][NH:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][C:36]([OH:40])=[CH:37][CH:38]=2)[N:33]([CH3:41])[C:32]=1[CH3:42])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:21]([O:20][C:19](=[O:25])[N:18]([C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:40][C:36]3[CH:35]=[C:34]4[C:39]([C:31]([C:29]([NH:28][CH3:27])=[O:30])=[C:32]([CH3:42])[N:33]4[CH3:41])=[CH:38][CH:37]=3)[CH:8]=2)=[O:12])[CH2:14]1)[CH3:26])([CH3:24])([CH3:23])[CH3:22]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](N(C)C(=O)OC(C)(C)C)C5)sc34)ccc12
Yield: 39.5 %

Procedure:
This material was prepared by the reaction of tert-butyl (3R)-1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl(methyl)carbamate 34c (0.181 g, 0.46 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.10 g, 0.46 mmole) and Cs2CO3 (0.149 g, 0.46 mmole) in a manner as previously described for example 1 to give a yellow solid (0.105 g, 40%). 1H NMR (300 MHz, CDCl3) δ8.48 (1H, d, J=5.4 Hz), 7.82 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.15 (1H, d, J=2.1 Hz), 7.02 (1H, dd, J=2.1, 8.7 Hz), 6.56 (1H, d, J=5.4 Hz), 5.91 (1H, d, J=4.7 Hz), 4.82 (1H, m), 4.07 (2H, m), 3.87 (1H, m), 3.68 (1H, m), 3.65 (3H, s), 3.05 (3H, d, J=4.7 Hz), 2.84 (3H, s), 2.73 (3H, s), 2.17 (2H, m), 1.45 (9H, s); HRMS (MH+): Calcd: 578.2450; Found: 578.2437.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][C:21](OC)=[O:22])=[C:10]1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:22])=[C:10]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: C1CNCCN1
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(C)N1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(CC(=O)N2CCNCC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of dimethyl 4-(2,6-dichlorophenyl)-2-methoxycarbonylmethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate(13.9 g, 30 mmol) , piperazine(39.2 g, 460 mmol), and dimethylformamide(30 ml) was heated to 100° C. (becomes a solution) and stirred for 1.5 h (longer reaction times result in decomposition). The reaction mixture was cooled briefly, poured into water(800 ml), and extracted with ethyl acetate. The extract was washed thoroughly with water, dried over sodium sulfate, and concentrated to give 12.2 g (84%) of an orange color oil, suitable for use in succeeding steps. It can be purified by column chromatography on silica gel using dichloromethane/methanol: 2/1 as eluent.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:12][N:11]1[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[C:19]([O:18][C:16]([N:14]1[C@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:12][N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C@@H:10]([CH2:9][OH:8])[CH2:15]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2COCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2CO)cc1
Yield: 99.7 %

Procedure:
Palladium hydroxide on carbon (700 mg) was added to a solution of (2R,5R)-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine (6.4 g) in MeOH (60 ml), and the mixture was hydrogenated in hydrogen at 3.5 atm for 4 hours at ambient temperature. The catalyst was removed by filtration through a celite pad and the filtrate was washed with MeOH. The filtrate and combined washings were concentrated in vacuo to give 5.3 g of (2R,5R)-4-(tert-butoxycarbonyl)-2-hydroxymethyl-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine as white crystals.
Reaction SMILES: [NH4+:1].[Cl-].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=O)=[CH:6][CH:5]=1>>[CH:6]1[C:7]([C:8]#[N:1])=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Cl-]
Product: N#Cc1ccc(Cl)cc1
Temperature: 220 °C

Procedure:
A 2 L glass resin kettle was fitted with an overhead stirrer, glass thermocouple well, and a 15 cm (6 inch) 24/40 U-connector tube wrapped with an electrical heating tape and set at a 120° to 150° C. skin temperature. The U-connector tube was attached to a 1 L, 3-necked, round bottom flask fitted with an air condenser, which was used as a sublimate trap to a stop the easily sublimed product. To this was added either 1.1 eq. (first two runs) or 1.0 eq. (last three runs) NH4Cl, 7.50 g MgO (0.5 wt % based on the PCBTC) and 1500 g of 99 wt % PCBTC. The kettle was heated with a mantle to 220° C. The temperature was controlled using an Instruments for Research and Industry "Therm-O-Watch" model L11-1500 temperature controller with a K-type thermocouple. Samples were removed periodically and were analyzed by gas chromatograph (GC). Because p-chlorobenzoylchloride (PCBOC) has the same boiling point as PCBN but a slower reaction rate, the reaction was continued until all of the PCBOC had been consumed. In general, when less than 5 wt % of PCBTC remained (after 15 to 20 hours of reaction at 220° C.) the 1 L sublimate receiver was exchanged for a clean one and the product was up and over distilled. After cooling the reactor, it was recharged with the sublimate from the previous run, NH4Cl, and PCBTC, and the sequence was repeated. In this manner, 7 kg of PCBTC gave a 90.5 wt % isolated yield of PCBN with an average purity of 97 wt % by GC area%.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([NH:6][S:7]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=1)(=[O:9])=[O:8])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[CH2:1]([N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]=[C:10]1[S:7]([NH:6][CH2:4][CH3:5])(=[O:9])=[O:8])[CH3:2]
Reactant: CCI
Reactant: CCNS(=O)(=O)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCNS(=O)(=O)c1nc2ccccc2n1CC
Yield: 74.7 %

Procedure:
46.8 g (0.3 mol) of ethyl iodide are added to a suspension of 67.5 g (0.3 mol) of N-ethyl-1H-benzimidazole-sulfonamide and 47.7 g (0.45 mol) of sodium carbonate In 450 ml of acetone and 20 ml of water. The mixture is left under reflux for 20 hours, the acetone is evaporated off, 200 ml of water are added and the product is extracted with methylene chloride. The organic layer is dried (Na2SO4) and evaporated. The residue is recrystallized from an ethanol/water mixture (2:1) to give 56.8 g (75%) of 1,N-diethyl-1H-benzimidazole-2-sulfonamide melting at 135°-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:46][CH2:47][N:48]([C:27]([N:9]2[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:12]=[C:8]2[C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]=2[O:30][CH2:31][CH3:32])=[O:28])[CH2:49][CH2:50]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
N-tert-Butyl-2-{4-[(4S,5R)-2-[5-chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 16g) in an analogous manner as described in example 25. LR-MS: 737.4 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2ccccc2n1
Yield: 60.5 %

Procedure:
To a mixture of 2-methylquinazolin-4(3H)-one (9.2 g, 0.0574 mol) and phosphorous oxychloride (5.8 g, 0.037 mol) in dry toluene (250 ml) was added N,N-dimethyl aniline (13.9 g, 0.14 mol) and the mixture was refluxed for 3 h. The reaction mixture was cooled and washed with water, brine and dried. The solvent was removed under vacuum and the residue was purified by chromatography (silica gel, 60-120 mesh) eluting with pet ether/ethyl acetate (9/1) to afford 4 g (39%) of the titled compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[S:19][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[Br:33][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]2[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:19][C:10]=2[C:11]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)cn2C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution (0.1 M) of methyl 4-(tert-butoxycarbonyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM was cooled to 0° C. and treated with NBS (1.1 eq.) then it was left to warm to RT. The reaction was quenched with aqueous Na2S2O3 (saturated solution) and extracted with AcOEt. The organic phase was washed with aqueous Na2S2O3 (saturated solution) and brine then dried and concentrated, affording the title compound (98%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C1COCC1>[Br:12][C:3]1[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][NH:6][C:2]=1[NH2:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(-c2cccs2)n[nH]1
Solvent: C1CCOC1
Product: Nc1[nH]nc(-c2cccs2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a stirring solution of 5-amino-3-(2-thienyl)pyrazole (500 mg, 3.03 mmol) in THF (10 mL) was added N-bromosuccinimide (592 mg, 3.33 mmol) in one portion. The reaction mixture was stirred at room temperature for 3 h, then the solvent was evaporated and the residue was taken up in ethyl acetate. The organic layer was washed successively with 1M aqueous sodium thiosulfate, twice with a saturated aqueous solution of sodium bicarbonate, and brine, then it was dried over sodium sulfate, filtered, and adsorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 686 mg (93%) of 4-bromo-5-thiophen-2-yl-2H-pyrazol-3-ylamine as a dark foam. 1H-NMR (d6-DMSO) δ: 11.9 and 12.4 (2 broad s, 1H, NH+tautomer), 7.4-7.65 (m, 2H), 7.05-7.2 (m, 1H), 4.8 and 5.3 (2 broad s, 2H, NH2+tautomer).
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:36])[C@H:31]([CH2:33][CH2:34][CH3:35])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:36])[C@H:31]([CH2:33][CH2:34][CH3:35])[NH2:32])=[O:17])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CCC[C@H](N)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 146.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (155 mg, 0.53 mmol, 1.0 eq), L-norvaline N-benzylamide (220 mg, 1.07 mmol, 2.0 eq) and dichloromethane (1.0 mL), was treated with triethylamine (446 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (680 uL, 1.07 mL, 2.0 eq), to provide 372 mg (70%) of L-norvaline, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[OH:25][CH2:26][C@H:27]1[O:32][CH2:31][CH2:30][N:29]([C:33]2[S:34][CH2:35][C:36](=[O:38])[N:37]=2)[CH2:28]1>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[C:35]3[S:34][C:33]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][OH:25])[CH2:28]4)=[N:37][C:36]3=[O:38])[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:22])([F:23])[F:24])[N:3]=1
Reactant: O=C1CSC(N2CCO[C@H](CO)C2)=N1
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C1N=C(N2CCOC(CO)C2)SC1=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-(2-(S)—Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following general procedure D.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][CH:19]=[N:18]4)[N:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[CH:20][C:19]([C:1]3([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:18]4)[N:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: c1cnc2c(c1)ccc1ccc(C3CCCCC3)nc12
Reactant: O=C1CCCCC1
Product: OC1(c2ccc3ccc4ccc(C5CCCCC5)nc4c3n2)CCCCC1
Yield: 60 %

Procedure:
By following General Procedure I, cyclohexanone (0.094 g, 0.953 mmol) was added to 2-(cyclohexyl)-1,10-phenanthroline, prepared as described by Example 15, (0.100 g, 0.381 mmol) and 0.1 M SmI2 (8.38 mL, 0.838 mmol) yielding 0.083 g (60% yield) of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3) δ8.24 and 8.14 (two d, J=8.40 Hz, Hp3 and Hp9), 7.76 and 7.70 (two d, J=8.80 Hz, Hp5 and Hp6), 7.66 and 7.52 (two d, J=8.40 Hz, Hp4 and Hp7), 3.06 (tt, J=11.85, 3.30 Hz, (CH2)5CH (phenan)), 2.18-1.74 (m, 10H), 1.52-1.33 (m, 10H); 13C NMR (75 MHz) δ166.98, 165.25, 144.88, 143.44, 137.16, 136.01, 127.49, 127.28, 126.21, 124.85, 121.47, 118.65, 73.16, 47.24, 36.75, 32.81, 26.64, 26.12, 25.75, 22.71; IR (CHCl3) 3338 (OH), 3042 (C—H Ar), 2927 (CH), 852 (C—H Ar) cm−1; HRMS m/e Calcd for C24H29N2O (MH+): 361.2280, found, 361.2272.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:10]=[CH:9][N:8]=1)=[O:5])[CH3:2].[Br:20]NC(=O)CCC(N)=O>CN(C=O)C>[Br:20][C:10]1[C:11]([C:13]2[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:8][CH:9]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCNC(=O)Nc1cc(-c2ccc(F)nc2)ccn1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2ccc(F)nc2)c(Br)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of N-ethyl-N′-(6-fluoro-3,4′-bipyridin-2′-yl)urea (Intermediate 32, 360 mg, 1.38 mmol) in DMF (7 mL), N-bromosuccinamide (246 mg, 1.38 mmol) was added. The resulting solution was heated to 80° C. and stirred at that temperature for 2 hours. Then the reaction was partitioned between water and ethyl acetate. The layers separated, and the organic layer was washed with 5% sodium thiosulfate solution, water and brine, then dried over magnesium sulfate and concentrated. The solid obtained was washed with acetonitrile and dried to give the title compound as an off-white solid (390 mg). MS (ESP): 340 (M+1) for C13H12FN4O; NMR: 1.07 (t, 3H); 3.12-3.18 (m, 2H); 7.36-7.40 (m, 2H); 7.68 (s, 1H); 8.15 (t, 1H); 8.34 (d, 1H); 8.47 (s, 1H); 9.36 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][O:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(Cl)C.S(Cl)(Cl)=O.[OH-].[Na+]>>[CH3:14][CH:2]([CH3:1])[CH2:3][O:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]([CH2:9][CH3:10])[CH2:12][CH3:11]
Reactant: CC(C)COCC(O)CN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCN(CC)CC(O)COCC(C)C
Temperature: 0 °C

Procedure:
10 g. 3-(2-Methylpropoxy)-1-pyrrolidinopropan-2-ol are dissolved in 100 ml. dichloroethane. A solution of 7.1 g. thionyl chloride in 20 ml. dichloroethane is added dropwise thereto, while stirring, and the reaction mixture subsequently heated for 2 hours to 70° C. The reaction mixture is cooled, poured on to ice water and subsequently rendered alkaline by the addition of a concentrated aqueous solution of sodium hydroxide. The organic phase is separated off and the aqueous phase again extracted with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate and evaporated. The residue is purified by chromatography on a silica gel column (elution agent: methylene chloride/5% methanol). There are obtained 9 g. of the title compound in the form of an oily product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][CH2:49][OH:50])[CH:46]=2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O.N.CO>>[OH:50][CH2:49][CH2:48][CH2:47][N:45]1[CH:46]=[C:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH:43]=[N:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (897 mg, 1.98 mmol) and 7-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 289A, 633.5 mg, 2.212 mmol). in TFE (12 mL) was charged with TFA (654.2 mg, 5.737 mmol) and irradiated by microwave heating [Biotage, 105° C.] for 1 h. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo. The residue was dissolved in MeOH (unmeasured amount), cooled to 0° C., and charged with 7.0 M of NH3 in MeOH (5 mL, 40 mmol). After stirring from 0° C. to rt over 1 h 45 min, the suspension was concentrated in vacuo and the crude product purified using a Teledyne/ISCO Combiflash system eluting with a solvent system of 0-10% MeOH:CH2Cl2 to afford the title material as a white solid, 1.1017 g (78%). 1H NMR (400 MHz, DMSOd6) δ 10.72 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.06-8.63 (m, 1H), 7.96 (s, 1H), 7.70 (d, J=8.84 Hz, 1H), 7.41 (d, J=7.07 Hz, 1H), 7.10 (br. t, J=2.00 Hz, 1H), 6.96 (br td, J=2.30, 8.00 Hz, 1H), 4.53-4.67 (m, 3H), 4.21 (t, J=7.20 Hz, 2H), 4.00 (qd, J=7.06, 8.12 Hz, 4H), 3.74 (s, 3H), 3.43 (q, J=6.06 Hz, 2H), 3.36 (d, J=19.96 Hz, 2H), 3.11 (s, 3H), 1.97 (quin, J=6.63 Hz, 2H), 1.17 (t, J=6.95 Hz, 6H). MS (ES+): m/z 704.23 (100) [MH+]. HPLC: tR=3.73 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4]OS(C)(=O)=O.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K].O>CN(C=O)C>[F:1][CH2:2][CH2:3][CH2:4][N:14]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCCF
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCF
Temperature: 75 °C
Yield: 99.1 %

Procedure:
A solution of methanesulfonic acid 3-fluoro-propyl ester (34.5 g, 221 mmol) in 250 mL of anhydrous DMF was treated with solid potassium phthalimide (49 g, 265 mmol, 1.2 equiv) at 25° C. The resulting suspension was warmed to 70-80° C. for 2 hours. When 1H NMR showed that the reaction was complete, the reaction mixture was treated with H2O (200 mL). The aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired 2-(3-fluoro-propyl)-isoindole-1,3-dione (45.4 g, 45.5 g theoretical, 99.7% yield) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.CS(O)(=O)=O.[N-:17]=[N+]=[N-].[Na+].[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:17][CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
To 25.0 g (166.15 mmol) 5-fluoroindanone in a 3 L flask equipped with a mechanical stirrer was added 280 ml dichloromethane and 200 ml methanesulfonic acid. The mixture was cooled to 0° C. and 15.15 g (233.1 mmol) sodium azide was added in portions over 20 minutes. The mixture was stirred at 0° C. for 2 h, then 490 ml 20% aqueous sodium hydroxide was added dropwise over 30 minutes. The layers were separated and the organic phase dried over MgSO4 and concentrated. Purification by column chromatography eluting with ethyl acetate/hexanes provided 16.76 g (61%) of the desired 6-fluoro-3,4-dihydroisoquinolinone isomer.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClC(Cl)C.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCCCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCCCCC(C)Nc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A flask containing 4-iodoaniline (11.0 g, 50.2 mmol)was charged with dry dichloroethane (125 ml), 2-octanone (7.9 ml, 50.0 retool) and sodium triacetoxyborohydride (13.8 g, 65 retool). After stirring for 10 minutes, acetic acid (2.9 ml, 50.7 retool) was added via syringe over a 5 minute period. The reaction was stirred under an N2 atmosphere for 16 hrs. At the end of this period the reaction was quenched by the careful addition of a solution of saturated aqueous ammonium chloride (100 ml). After stirring for 0.5 hr, the reaction was poured over ether (250 ml) andthe layers were separated. The ether layer was washed with saturated aqueous ammonium chloride (100 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:39; EtOAC:hexanes) provided N-(4'-iodophenyl)-2-amino octane (14.6 g, 88%) as a light yellow oil.