Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:11][CH2:12][CH2:13]Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[Na]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:11][CH2:12][CH2:13][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(SCCCl)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: Clc1ccc(C2=NOCCS2)cc1

Procedure:
2-Chloroethyl 4-chloro-N-hydroxybenzenecarboximidothioate (2.5 g, 0.01 mol) was cyclised with sodium (0.23 g) in ethanol (25 ml) as described in Example 2. 3-(4-Chlorophenyl)-5,6-dihydro-1,4,2-oxathiazine, mp 80.5°-81.5° C., was isolated. (Found: C,50.16; H,4.24; N,6.44. C9H8ClNOS requires C,50.58; H,3.77; N,6.55.)
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].C(Cl)Cl>CCCCCC>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1cc(N)ccc1Sc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 904.2 %

Procedure:
To a stirred slurry of 4-nitro-2-cyanophenyl phenyl sulfide (13.3 g, 5.19 mmol) and 100 mL of absolute ethanol was added stannous chloride dihydrate (58.6 g, 26 mmol) in one portion. The mixture was heated to 60° C. where an exothermic reaction caused the solution to strongly reflux. The mixture was allowed to stir at ambient temperature for 30 min., poured onto ice-water and made strongly basic by the addition of 350 mL of 15% NaOH. The mixture was extracted with methylene chloride (4×275 mL), the extracts dried (MgSO4), filtered, and the solvent removed in vacuo to yield an oil which was chromatographedon 300 g of silica gel using a methylene chloride (20%, 40%, 60% 80% and 100%) in hexane gradient. The proper fractions were combined and the solvent removed to yield the 4-amino-2-cyanophenyl phenyl sulfide (10.62 g, 91%) as a pale yellow solid; mp 73°-75° C. 1H-NMR (300 MHz, CDCl3): 4.01 (s, 2H, NM2), 6.78 (dd 1H, J=8.5, 2.6, aromatic), 6.95 (d, 1H, J=2.6, aromatic), 7.18-7.29 (m, 5H, aromatic), 7.34 (d, 1H, J=8.5, aromatic). MS (CI, CH4):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17](=O)[CH2:16][O:15][C:14]([CH3:21])([CH3:20])[C:13]=3[CH:22]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:17](=[S:32])[CH2:16][O:15][C:14]([CH3:21])([CH3:20])[C:13]=3[CH:22]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(F)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OCC(=S)Nc2ccc(-c3cc(F)cc(F)c3)cc21

Procedure:
Prepared from 7-(3,5-difluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and Lawesson's Reagent using the procedure of example 10. 1H-NMR (DMSO-d6) δ 12.01 (s, 1H), 7.70-7.63 (m, 2H), 7.59-7.48 (m, 2H), 7.41 (d, J=8.82 Hz, 1H), 7.28-7.18 (m, 1H), 4.51 (s, 2H), 1.62 (s, 6H); MS (FI) m/z 318 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[N:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:5]2[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: Oc1cncc(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cncc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 5-(trifluoromethyl)pyridin-3-ol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (16.0 g, 72.2 mmol) in tetrahydrofuran (150 mL) was added N,N-dimethylformamide (0.1 mL), and oxalyl chloride (7.2 mL, 84.0 mmol) was further added dropwise at 0° C., and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure to dryness to give 2-chloro-3-(1-cyanocyclopropyl)benzoyl chloride as a pale-yellow oil.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][C:18]#[N:19])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][N:5]=1.[CH2:20](N)[CH2:21][NH2:22]>C(O)C.ClCCl>[CH3:2][S:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][C:18]3[NH:22][CH2:21][CH2:20][N:19]=3)=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: NCCN
Reactant: COc1cc2c(SC)ncnc2cc1OCC#N
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(SC)ncnc2cc1OCC1=NCCN1
Temperature: 4 °C
Reaction time: 20 h
Yield: 16 %

Procedure:
Excess anhydrous hydrochloric acid in ethanol (1 ml) was added to a solution of 4-(methylthio)-6-methoxy-7-(cyanomethoxy)quinazoline (300 mg, 1.15 mmol) in dichloromethane (20 ml) and the reaction was stirred for 20 hours at 4° C. The solvent was evaporated, ethylene diamine (280 mg, 8.15 mmol) in ethanol (10 ml) was added to the residue, and the mixture was refluxed for 2 hours. Solvent evaporation in vacuo and purification by flash chromatography on silica gel, eluting with 5% methanol in dichloromethane, yielded 4-(methylthio)-6-methoxy-7-((4,5-dihydro-2-imidazolyl)methoxy)quinazoline (56 mg, 22% yield) as a white solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=O)[C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[N:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]ncc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cnnc(Cl)c2-c2ccncc2)cc1

Procedure:
5-(4-Fluorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one was reacted with POCl3 using procedures analogous to those described in Example 273C to give the title compound, 3-chloro-5-(4-fluorophenyl)4-(pyridin-4-yl)pyridazine. LC/MS (method A): RT=1.43 min, (M+H)+=286.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1[C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]2[C:26]([O:28][C:29](=O)[C:19]=2[CH:18]=1)=[O:27]>C(O)(=O)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:4]1[CH:3]=[C:2]([N:1]2[C:26](=[O:27])[C:20]3[C:19](=[CH:18][CH:17]=[C:22]([C:23]([OH:25])=[O:24])[CH:21]=3)[C:29]2=[O:28])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1cccc(-c2nc3ccccc3o2)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccccc4o3)c1)C2=O
Yield: 77 %

Procedure:
2-(3-Aminophenyl)benzoxazole (500 mg, 2.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (546 mg, 2.4 mmol) in acetic acid (25 ml) were heated to reflux overnight. On cooling the precipitate was filtered, washed with acetic acid and dried to give the title compound 710 mg (71%). 1H NMR (CDCl3) δ 8.44(dd, J=1.5, 7.9 Hz, 1H), 8.36(d, J=4.5 Hz, 2H) 8.28(dt, J=1.5, 7.2 Hz, 1H), 8.12(d, J=7.9 Hz, 1H), 7.86–7.39(m, 4H), 7.45(m, 2H). MS 383 m/z (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[N:10]([C@@H:16]([CH2:26][CH3:27])[CH2:17][N:18]([CH3:25])[S:19]([CH:22]3[CH2:24][CH2:23]3)(=[O:21])=[O:20])[C@@H:9]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:44][CH2:45][CH:46]=[CH2:47]>C1COCC1>[CH2:44]([C:12]1([CH3:14])[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:10]([C@@H:16]([CH2:26][CH3:27])[CH2:17][N:18]([CH3:25])[S:19]([CH:22]2[CH2:23][CH2:24]2)(=[O:21])=[O:20])[C:11]1=[O:15])[CH2:45][CH:46]=[CH2:47]
Reactant: C=CCCBr
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-((2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (2618 mg, 5.0 mmol; Example 201, Step B) in degassed THF (10 mL) was added lithium diisopropylamide (5.00 mL, 10.00 mmol) at −15° C. After stirring at −15° C. for 30 min, the reaction mixture was cooled to −74° C. 4-Bromobut-1-ene (1.066 mL, 10.50 mmol) was added slowly. The reaction mixture was stirred at −74° C. for 3 h before warming up to rt and then stirred at rt for 66 h. Filtered and purified by HPLC (C18 column, eluted with 10 to 95% CH3CN in water, with 0.1% TFA) to give the title compound as the first eluting isomer Its stereoisomer is obtained as the later eluting isomer.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:21]([OH:26])[OH:22])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 4-tert-butyldimethylsilyloxybromobenzene (11.49 g) in tetrahydrofuran (100 ml) was added a solution of n-butyllithium in n-hexane (1.59M, 32.7 ml) dropwise at −55° C. under a nitrogen atmosphere, and the mixture was stirred for 1 hour at −60° C. To the reaction mixture was added triisopropyl borate (12.84 ml), and the mixture was stirred at −60° C. for 1 hour. The reaction mixture was warmed to ambient temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The solid was triturated with n-hexane, filtered and washed with n-hexane to give 4-tert-butyldimethylsilyloxyphenylboronic acid (7.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C@@H:29]1[CH2:53][CH2:52][C@@:51]2([CH3:54])[CH:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:55])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[C@H:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:30]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:28][C@@H:29]1[CH2:53][CH2:52][C@@:51]2([CH3:54])[CH:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:55])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[C@H:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:30]1)=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@H](Cc5ccc(OCc6ccccc6)cc5)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 83.5 %

Procedure:
By using N-tert-butyloxycarbonyl-O-benzyl-L-tyrosine (500 mg, 2.03 mmol) and 3α-aminocholestane (866 mg, 2.23 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (1.13 g, yield; 83.5%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=[O:5].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[F:22])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)c(Br)cc1Br
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Oc2ccc([N+](=O)[O-])cc2F)c(Br)cc1Br
Yield: 70.6 %

Procedure:
2,4-Dibromo-5-hydroxy-benzaldehyde (50 g, 178.6 mmol), 1,2-difluoro-4-nitrobenzene (28.4 g, 178.6 mmol) and potassium carbonate (49.0 g, 357.2 mmol) are stirred in DMF (500 mL) at 60° C. for 2 hours. The reaction is quenched with water (1000 mL) and extracted with methyl tert-butylether (MTBE) (2×500 mL). The organic layer is washed with saturated sodium chloride aqueous solution (2×500 mL), dried with anhydrous sodium sulfate, and concentrated to obtain a yellow solid. The crude solid is recrystallized in EtOAc/PE (1:5) to give 2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)benzaldehyde as a yellow solid (52.8 g, 70.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O-2].[Mg+2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([N:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: CN(C)C=O
Product: Brc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 47 h
Yield: 63.4 %

Procedure:
A mixture of 16 g of 3-bromoaniline, 15 g magnesium oxide and 31.8 g benzylbromide in 100 mL dry dimethylformamide was stirred for 47 hours at room temperature, under nitrogen. The precipitated magnesium salts were filtered. The filtrate was diluted with water and extracted with ether. The ether extracts were combined, washed with water and dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the ether evaporated in vacuo to give a brownish solid. The brownish solid was recrystallized from isopropanol to yield 20.75 g of N,N-dibenzyl-3-bromoaniline as a white solid. The structure was confirmed by NMR.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(O)C.[OH-].[Na+]>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][N:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCC(C)=O
Product: O=C(O)CCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 13.3 %

Procedure:
A mixture of 3,4-diphenylpyrazole (2.2 g), ethyl 8-bromooctanoate (5.5 g) and potassium carbonate (3.7 g) in dry butanone (50 ml) was heated at reflux temperature for 44 hours. The mixture was filtered and the filtrate evaporated to an oil which was chromatographed on silica gel (hexane/ethyl acetate). The oil obtained was heated at reflux temperature in a mixture of ethanol and 2N sodium hydroxide (1:1) for 1 hour. The ethanol was evaporated and the aqueous residue was acidified with dilute hydrochloric acid to pH 3, extracted with dichloromethane, dried over magnesium sulphate and evaporated to a solid. This was recrystallised from dichloromethane/ether to give 8-(3,4-diphenylpyrazol-1-yl)octanoic acid (0.48 g, 13%) as colourless crystals, m.p. 114°-5° C. Found: C, 76.02; H, 7.25; N, 7.63%; C23H26N2O2 requires: C, 76.21; H, 7.23; N. 7.73%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:19]Br.C(N(C(C)C)CC)(C)C>C(#N)C.CN(C)C=O.ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1)[CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[N:10][N:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1nnc(NC2CCNCC2)s1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1nnc(NC2CCN(Cc3cc(F)cc(C(F)(F)F)c3)CC2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.5 %

Procedure:
A mixture of 5-(piperidin-4-ylamino)-[1,3,4]thiadiazole-2-carbonitrile (D6) (0.16 g, 0.76 mmol), 3-fluoro-5-(trifluoromethyl)benzyl bromide (0.124 ml, 0.76 mmol) and diisopropylethylamine (0.20 ml, 1.14 mmol) in acetonitrile (2 ml) and N,N-dimethylformamide (0.5 ml) was stirred at room temperature for 48 h. After this period, the reaction mixture was diluted with dichloromethane and extracted with a saturated solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 2-3% ammonia in methanol (7M)/dichloromethane) to yield E18 (0.019 g, 7%) as a solid. C16H15F4N5S requires 385. Found 386 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[CH3:8][C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26](O)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[C:13]=2[CH:12]=[C:11]2[O:30][CH2:31][O:32][C:10]=12.S(Cl)(Cl)(=O)=O.S(Cl)(Cl)=O.C[N:43](C)C=O.[OH-].[NH4+]>>[F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[CH3:8][C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH2:43])=[CH:22][CH:21]=3)[C:13]=2[CH:12]=[C:11]2[O:30][CH2:31][O:32][C:10]=12
Reactant: CN(C)C=O
Reactant: Cc1c2c(cc3c1OCO3)C(c1ccc(S(=O)(=O)O)cc1)CNCC2
Agent: NC(=O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: Cc1c2c(cc3c1OCO3)C(c1ccc(S(N)(=O)=O)cc1)CNCC2

Procedure:
The sulfonic acid (750 mg) is converted to the sulfonyl chloride using thionyl chloride/dimethylformamide then reacted without purification with an excess of ammonium hydroxide to give 6-methyl-7,8-methylenedioxy-1-(p-sulfamylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide. Alkaline hydrolysis of the acetamide (500 mg) and boron tribromide treatment of the residue in the cold gives the desired 6-methyl-7,8-dihydroxy-1-(p-sulfamylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: CS(C)=O.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:23]([C:39]#[N:40])=[C:24]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[S:25][C:26]=1[C:27]1[NH:28][CH2:29][CH:30]([CH3:32])[N:31]=1.[OH-].[NH4+]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:23]([C:39]#[N:40])=[C:24]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[S:25][C:26]=1[C:27]1[NH:28][CH:29]=[C:30]([CH3:32])[N:31]=1
Reactant: CC1CNC(c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)=N1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c[nH]c(-c2sc(N3CCOCC3)c(C#N)c2-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To DMSO (32.0 uL, 0.000451 mol) in DCM (3 mL, 0.05 mol) at −78° C. was added oxalyl chloride (38.2 uL, 0.000451 mol) and the mixture was stirred for 30 min. 4-(2,4-dichlorophenyl)-5-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (19 mg, 0.000045 mol) in DCM (1.5 mL, 0.023 mol) was added. After 1 h, TEA (0.188 mL, 0.00135 mol) was added and the mixture was stirred for another 30 min. 33% ammonium hydroxide (33:67, ammonia:Water, 0.117 mL) was added and the reaction mixture was warmed to room temperature. The mixture was purified by column chromatography to afford 4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)-2-morpholinothiophene-3-carbonitrile (4.04 mg, 21%). LCMS: (FA) ES+ 419.13, ES− 417.17. 1H NMR (400 MHz, d1-chloroform) δ: 7.61 (d, 1H), 7.42 (dd, 1H), 7.34 (d, 1H), 6.61 (s, 1H), 3.88-3.84 (m, 4H), 3.62-3.57 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:16]([Mg]Br)=[CH2:17].Cl>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]([OH:10])([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:16]=[CH2:17])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C=C[Mg]Br
Reactant: O=C(c1cc(F)cc(F)c1)c1nccs1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)(c1cc(F)cc(F)c1)c1nccs1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of (3,5-difluorophenyl)(thiazol-2-yl)methanone (1 g, 4.4 mmol, Step 2) in dry THF (40 mL) was added at 0° C. (4.4 mL, 4.4 mmol) of a 1.0M THF solution of vinyl magnesium bromide (Aldrich). The reaction mixture was stirred for 30 min. and then transferred to a 1N aqueous HCl solution. The resulting mixture was extracted with EtOAc and the combined organic phase were washed with brine, dried over MgSO4 and evaporated to give a residue which was chromatographed on silica gel eluting with 85:15 mixture of hexane:EtOAc to afford 635 mg (56%) of the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:23][C:24]4[N:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc2cnc(S(C)(=O)=O)nc2n(C2CCCC2)c1=O
Reactant: Nc1ccc(N2CCC(O)CC2)cn1
Solvent: ClCCl
Product: CCc1cc2cnc(Nc3ccc(N4CCC(O)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 140 °C
Yield: 7.3 %

Procedure:
8-Cyclopentyl-6-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.115 g, 0.47 mmol) and 6′-amino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ol (0.117 g, 0.61 mmol) were combined in dry xylenes and heated at 140° C. under nitrogen overnight. The crude reaction mixture then was allowed to cool and diluted with CH2Cl2. A precipitate was collected by filtration and dried in vacuo to give 8-cyclopentyl-6-ethyl-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (15 mg, 7%). MS (APCI); M++1: Calc'd, 435.2. Found 435.2.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:52][O:53][C:54]([CH:56]1[CH2:60][N:59]([C:61]([O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:62])[CH:58]2[CH2:71][CH2:72][NH:73][CH:57]12)=[O:55]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:52][O:53][C:54]([CH:56]1[CH2:60][N:59]([C:61]([O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[O:62])[CH:58]2[CH2:71][CH2:72][N:73]([C:16](=[O:18])[CH:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[CH:57]12)=[O:55]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCNC12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.3 %

Procedure:
A solution of Boc-L-cyclohexylglycine (257 mg, 1 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (380 mg, 1 mmol) followed by DIPEA (0.3 mL, 1.7 mmol). After 10 min, 15 (309 mg, 1.0 mmol) in NMP (5 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to afford 16 as an orange-colored foam (578 mg) which was used without further purification. Mass spectrum, m/z [544.4] (M+H)+.