Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[N:25]1([S:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[N:25]1([S:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:16]([C:11]3[CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[C:14]([CH3:15])=[CH:13][CH:12]=3)=[O:18])=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc(C#N)cc1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)N3CCOCC3)cc2)cc1-c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
To a suspension of 4′-cyano-6-methyl-biphenyl-3-carboxylic acid 3 (40 mg, 0.17 mmol) in anhydrous methylene chloride (5 ml) is added 2 drops of DMF. Then oxalyl chloride (32 mg, 22 μl, 0.25 mmol) is added. The mixture is stirred at ambient temperature until it turns clear. After that, it is concentrated, re-dissolved in anhydrous methylene chloride (3 ml), and added to a solution of 4-(morpholine-4-sulfonyl)-phenylamine (61 mg, 0.25 mmol) and triethylamine (34 mg, 47 t, 0.33 mmol) in methylene chloride (2 ml). The mixture is stirred for 2 hours, concentrated and the residue is purified by preparative mass triggered HPLC (C1-8 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid [4-(morpholine-4-sulfonyl)-phenyl]-amide: 1H NMR (DMSO-d6) δ 10.64 (s, 1 H), 8.07 (d, 2 H, J=8.8 Hz), 7.97 (d, 2 H, J=8.4 Hz), 7.95 (d, 1 H, J=8.8 Hz), 7.89 (s, 1 H), 7.43 (d, 2 H, J=8.4 Hz), 7.67 (d, 2 H, J=8.8 Hz), 7.53 (d, 2 H, J=8.8 Hz), 3.63 (m, 4 H), 2.84 (m, 4 H) 2.32 (s, 3 H); LC-MS m/z: 462.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[C:10]([CH:12]([C:28](OCC)=[O:29])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)#[N:11]>C(O)C>[NH2:4][C:3]1[NH:5][C:28](=[O:29])[C:12]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:10]([NH2:11])[N:2]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1ccc(OCCCC(C#N)C(=O)OCC)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCCc2c(N)nc(N)[nH]c2=O)cc1
Yield: 92.9 %

Procedure:
Guanidine hydrochloride (4.18 g, 43.7 mmoles) was added to a solution of sodium ethoxide (65.6 mmoles) in ethanol (25 mL), and the mixture was treated with compound 1A (7.0 g, 21.9 mmoles) as a solution in ethanol (25 mL) and then refluxed for 7 hours. After cooling, the mixture was filtered, the solid residue was washed with 3 volumes (10 mL) of ethanol, and the combined filtrate and washings were treated with acetic acid to pH ~ 7.0. The filtrate was evaporated in vacuo to a viscous residue and treated with water (50 mL). Filtration gave a solid, which was washed with 3 volumes (10 mL) of water and dried at 50° C. in vacuo to give 6.76 g (93%) of compound 1B as a white solid. NMR (DMSO-d6) δ 1.28 (t, 3H, CH3 of ester), 1.75 (m, 2H, CH2 --CH2 -- CH2), 2.25 (t, 2H, CH2 --CH2CH2 --O), 3.97 (t, 2H, --CH2 --O), 4.25 (q, 2H, CH2 of ester), 5.7 (s, 2H, NH2), 5.93 (s, 2H, NH2), 6.98 (d, 2H, benzoate H's ortho to oxygen), 7.85 (d, 2H, benzoate H's ortho to carbonyl), 9.8 (br s, 1H, ring NH). The intermediate, compound 1B, was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=4)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Nc1ncc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 4-(3-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.72) (0.45 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.27 g, 65%). MS (ISP) 418.1 [(M+H)+]; mp 281° C.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1.[NH4+].[OH-]>C1(C)C(C)=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:2][C:3]([OH:5])=[O:4])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(O)CBr
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=C(O)CNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
Bromoacetic acid (5.34 g, 32.0 mmol, 0.5 eq) is added dropwise to 4-fluoro-2-nitro-phenylamine (10.0 g, 64.1 mmol, 1.0 eq) at 120° C. After the addition, the reaction mixture is stirred for 2 hours at 120° C. then xylene (10 mL) is added. The resulting reaction mixture is heated at 130° C. for 1 hour, then it is made alkaline with 25% ammonia aqueous solution. Xylene is removed under reduced pressure and the residue is diluted with water (100 mL). The mixture is filtered at 60° C. and the insoluble residue is extracted twice with 10% ammonia aqueous solution at 60° C. The aqueous layer is acidified with hydrochloric acid to pH 5, the precipitated product is filtered, washed with water and ethanol, dried under vacuum to afford (4-fluoro-2-nitro-phenylamino)-acetic acid as a red solid (2.98 g, 34% yield).
Reaction SMILES: C(C1C=C([CH2+]=NC2C=CC(OC3C=CN=C(C(NC)=O)C=3)=CC=2F)N(C2C=CC=C(CO)C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].[C:77]1(=[O:83])[O:82][C:80](=[O:81])[CH2:79][CH2:78]1>O1CCCC1>[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=3)=[CH:53][C:52]=2[F:68])[N:44]([C:69]2[CH:70]=[C:71]([CH:72]=[CH:73][CH:74]=2)[CH2:75][O:76][C:77](=[O:83])[CH2:78][CH2:79][C:80]([OH:82])=[O:81])[N:43]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: O=C1CCC(=O)O1
Agent: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COC(=O)CCC(=O)O)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
To a room temperature solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (0.45 g, 0.85 mmol) in tetrahydrofuran (43 mL) was added succinic anhydride (0.10 g, 1.00 mmol). The reaction mixture was allowed at stir at room temperature for 72 h. The reaction mixture was concentrated and the residue was triturated with hexanes. The resulting white powder was filtered and washed with hexanes. The solids were re-dissolved in EtOAc, washed with sat. aqueous ammonium chloride solution (2×15 mL), dried (NaSO4) and concentrated to afford 0.49 g (91%) of pure product. MS m/z 633.1 (M+H)+; Retention time (LC-MS): 3.29 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(C2=CCNCC2)cc1
Temperature: 90 °C

Procedure:
4-(4-Bromophenyl)-4-piperidinol (68 g, 0.27 mol) was added in small portions to a solution of trifluoroacetic acid (205 ml) at r.t. and the mixture was heated at 90° C. for 2 hr. Solvents were then removed in vacuum to give 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine as pale yellow oil. The yellow oil was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([C:8]([O:10]CC)=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Yield: 90.6 %

Procedure:
A solution of 670 mg (3.2 mmol) of ethyl 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 15) and 3.2 ml (3.2 mmol) 1N NaOH in 20 ml MeOH was heated at 100° C. in a microwave reactor for 2 h. The mixture was diluted with water and extracted with EtOAc. The EtOAc was washed with 1N NaOH. The combined aqueous layers were acidified with concentrated HCl and extracted 2 times with EtOAc, each extract being washed with brine. The combined EtOAc layers were dried over anhydrous MgSO4, filtered and the solvent was removed to give 535 mg of product as a solid. MS (ES) (M−H−): 183 for C7H5ClN2O2; NMR (d6-DMSO): 2.2 (s, 3H), 12.9 (s, 1H), 13.3 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>ClCCl>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([C:30]([F:29])([F:40])[F:41])=[CH:32][CH:33]=4)[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12)c1ccc(C(F)(F)F)cc1
Yield: 60.9 %

Procedure:
A mixture of 0.29 g (0.001 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 1.13 ml(0.014 mol) pyridine in 30 ml dichloromethane was stirred with 0.63 g(0.003 mol) p-trifluoromethyl benzoyl chloride for 18 hours at room temperature. Then another 0.63 g(0.003 mol) p-trifluoromethyl benzoyl chloride were added and stirring was continued at reflux temperature for 48 hours. After extraction with aqueous sodium hydroxide the organic solvents were distilled off and the residue was recrystallised from methanol to yield 0.28 g(60%) N-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-trifluoromethyl-benzamide as white crystals. MS m/e (%): 460 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:35][C:34]3[CH:37]=[CH:38][C:31]([Cl:30])=[CH:32][CH:33]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccc(Cl)cc2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccc(Cl)cc2)c1

Procedure:
The reaction of hydroxylamine 55 (1.98 g, 5 mmol) with 4-chlorobenzaldehyde (62) (0.70 g, 5 mmol) afforded, after workup, a light yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/petroleum ether as the eluant to obtain 1.97 g (3.74 mmol, 75%) of 73 as a light yellow gum: IR (CH2Cl2) 3440, 2980, 1700, 1625, 1590, 1550, 1475, 1300, 1215, 1110, 910, 840; 1H NMR 1.10 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 2.26 (s, 6H), 3.31 (s, 3H), 3.56 (t, J=4.8 Hz, 2H), 4.18 (m, 2H), 4.93 (septet, J=6.2 Hz, 1H), 5.06 (s, 1H), 6.79 (s, 1H) 7.28-8.33 (m, 9H); 13C NMR (CDCl3) δ 19.77, 19.89, 22.48, 22.71, 40.52, 59.32, 63.35, 67.74, 71.21, 103.29, 104.13, 119.97, 122.02, 129.05, 129.52, 129.81, 130.85, 134.35, 136.94, 145.43, 146.25, 149.25, 150.39, 167.56, 168.01. Anal. Calcd for C28H31N2O6Cl; C, 63.81; H, 5.88. Found: C, 63.86; H, 5.84.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:18](=[O:19])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 33.9 %

Procedure:
To a stirred solution of 2-isopropylaniline (200 mg, 1.5 mmol) in THF (9 mL) was added pyridine (0.24 mL, 3.0 mmol), then phenyl chloroformate (0.28 mL, 2.2 mmol) at rt. Some solid precipitated out. The mixture was stirred at rt for 4.5 h. Water was added to the reaction and it was extracted with EtOAc. The organic solution was washed with water (5 mL) and dried over MgSO4 and then filtered. The filtrate was concentrated in vacuo and crystallized from EtOAc-hexanes (1:9 v/v) to afford the title compound (130 mg, 34%). 1H-NMR (DMSO-d6) δ 9.45 (s, 1H), 7.44 to 7.36 (m, 2H), 7.35 to 7.28 (m, 2H), 7.25 to 7.14 (m, 5H), 3.27 (m, 1H), 1.17 (d, J=6.9 Hz, 2H); TLC Rf=0.33 (9:1 v/v hexanes-EtOAc).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:28]C)=[CH:26][CH:27]=5)[C:19]([CH3:30])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:30])=[C:20]([C:22]5[CH:27]=[CH:26][C:25](=[O:28])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1-c1ccc(=O)[nH]c1
Temperature: 90 °C
Yield: 43 %

Procedure:
To 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (72 mg, 0.18 mmol) in 1,4-dioxane (2 mL) was added 0.5 mL of an aqueous 4 M hydrochloric acid solution. The reaction mixture was heated to 90° C. for 30 minutes before being quenched with triethlyamine (0.5 mL) and evaporated to dryness. The residue was dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography. The resulting trifluoroacetic acid salt was dissolved in dichloromethane (5 mL) and washed with a saturated sodium bicarbonate solution (5 mL). The organics were dried over sodium sulfate and evaporated to dryness to yield the product (30 mg, 44%) ESI-MS m/z calc. 387.43. found 388.3 (M+1)+. Retention time 1.39 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.18 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.61-7.58 (m, 1H), 7.51 (m, 1H), 7.37 (m, 1H), 7.26-7.23 (m, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.36 (d, J=9.5 Hz, 1H), 4.55 (t, J=8.7 Hz, 2H), 3.19 (t, J=8.7 Hz, 2H), 2.27 (s, 3H), 1.49-1.46 (m, 2H), 1.11-1.09 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:17])[CH2:13][S:14]([CH3:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O>COCCO>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:17])[C:13]([S:14]([CH3:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)=O
Solvent: COCCO
Product: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21

Procedure:
A solution of 5'-fluoro-N-methyl-2'-methylsulphinylacetylformanilide (0.77 g) in 2-methoxyethanol (25 ml) was heated to reflux over 20 minutes. Ater heating under reflux at 128° for 45 minutes the mixture was evaporated in vacuo to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, m.p.225.5°-227° (0.69 g).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][N:13]([CH3:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].C(N1C2C=CC(C3C4C(=CC(N(C)C)=CC=4)C(=O)O3)=CC=2C2C1=CC=CC=2)C>C(OC(=O)C)(=O)C>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]3[C:20]4[C:16](=[CH:15][C:14]([N:13]([CH3:23])[CH3:12])=[CH:22][CH:21]=4)[C:17](=[O:18])[O:7]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CCn1c2ccccc2c2cc(C3OC(=O)c4cc(N(C)C)ccc43)ccc21
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc2c(c1)C(=O)OC2c1ccc2c(c1)OCO2
Yield: 6.1 %

Procedure:
Following a procedure similar to that described in Example 1, part A above, 7.5 g of 3,4-(methylenedioxy)benzaldehyde and 9.1 g of 3-dimethylaminobenzoic acid were interacted in acetic anhydride to obtain 0.9 g of 3-(3,4-methylenedioxyphenyl)-6-dimethylaminophthalide (Formula II: R=CH3 ; X=H; Y=1-[3,4-(OCH2O)C6H3 ]) a light yellow solid melting over the range 134°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([NH2:21])=[C:18]([NH2:20])[N:19]=2)=[N:6]1.Cl[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>ClCCl>[NH2:20][C:18]1[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:15]=[N:16][C:17]=1[NH:21][C:27](=[O:28])[O:29][CH3:30]
Reactant: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
200 mg (purity 67%, 0.398 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5,6-diamine were admixed with 4 ml of dichloromethane and cooled to 0° C. 151 mg (1.594 mmol) of methyl chloroformate dissolved in 1 ml of dichloromethane and 161 mg (1.594 mmol) of triethylamine were added and the mixture was stirred at RT for 15 min. The precipitate was filtered off with suction and dried under high vacuum. This gave 97 mg (61% of theory) of the target compound.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH2:17][O:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:31])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:31])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(COC(=O)c3ccc(OC)cc3)cccc2c1=O
Product: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Cl

Procedure:
A solution of 3-butyryl-8-(4-methoxybenzoyloxymethyl)-4(1H)-quinolone (5.75 g, 15.1 mmol) in phosphoryl chloride (75 ml) was heated at reflux for 30 minutes, the phosphoryl chloride evaporated in vacuo, the residue poured onto ice, neutralised with sodium bicarbonate, and extracted into dichloromethane. Drying, evaporation, and trituration with ether gave the crude 3-butyryl-4-chloro-8-(4-methoxy-benzoyloxymethyl)quinoline, which was used without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@@H:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6](=[O:20])[NH:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:10]=2[CH:9]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:17][N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([NH:7][C:6]([C@H:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:4][CH2:3][C:1]3[NH:31][N:30]=[N:29][N:2]=3)=[O:20])[CH:19]=[CH:18][C:11]=2[CH2:12][CH2:13]1
Reactant: CN1CCc2ccc(NC(=O)[C@@H](CCC#N)NC(=O)OC(C)(C)C)cc2CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCc2ccc(NC(=O)[C@@H](CCc3nnn[nH]3)NC(=O)OC(C)(C)C)cc2CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
200 mg (0.52 mmol) tert.butyl(R)-[3-cyano-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]carbamate are placed in 1 ml DMF and combined with 80 mg (1.23 mmol) sodium azide and 66 mg (1.23 mmol) ammonium chloride. The reaction mixture is stirred overnight at 100° C., then acidified with TFA and separated using RP material (eluant: water/acetonitrile 95:5=>5:95).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH:26]([C:28]1[S:32][CH:31]=[C:30](B(O)O)[CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:30]4[CH:29]=[C:28]([CH:26]=[O:27])[S:32][CH:31]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: O=Cc1cc(B(O)O)cs1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1csc(C=O)c1
Temperature: 80 °C

Procedure:
To 30 ml, of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (600 mg, 1.85 mmol), 5-formylthiophene-3-boronic acid (348 mg, 2.23 mmol), PdCl2(PPh3)2 (60 mg, 0.085 mmol), 1M Na2CO3 aqueous solution (7.4 mL, 7.4 mmol). The mixture was heated at 80° C. under N2 for 3.5 hours, cooled to room temperature and poured into 200 mL of water. The mixture was extracted with EtOAc (3×80 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde as brown solid. Yield: 458 mg, 70%.