Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].N1C=CC=CC=1.[C:39]1([CH3:49])[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][S:45]([C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([CH3:49])[CH:40]=3)(=[O:47])=[O:46])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2nccc(Oc3ccc4ccc(NS(=O)(=O)c5cccc(C)c5)cc4c3)c2cc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.168 g, 0.48 mmol) in 20 mL of CH2Cl2 was added K2CO3 (0.134 g, 0.96 mmol), and pyridine (1 mL). The mixture was cooled to 0° C. and m-toluenesulfonyl chloride (0.110 g, 0.58 mmol) was added and the solution was stirred for 16 h at RT under an atmosphere of nitrogen. The reaction was diluted with water and extracted with CH2Cl2 3×. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, treated with NaHCO3(aq) and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 501.0 (M+1). Mass Calc'd for C28H24N2O5S: 500.573.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Br:39])[CH:37]=3)[CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:39][C:36]1[CH:37]=[C:38]2[C:33]([CH:32]=[CH:31][N:30]=[C:29]2[O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[CH:34][CH:35]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2nccc3ccc(Br)cc23)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2nccc3ccc(Br)cc23)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(7-bromo-isoquinolin-1-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCC(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1cccs1)c1ccc(F)cc1
Yield: 94.4 %

Procedure:
20.8 g of N-[(2-thienylcarbonyl)methyl]amine hydrochloride, 40.0 g of sodium bicarbonate and 18.5 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 29 g of N-(4-fluorobenzoyl)-N-[(2-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [Br:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[C:4](=[O:12])[O:3]1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[Br-:1].[Br:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4](=[O:12])[O:3][CH:2]2[P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C1OC(Br)c2cc(Br)ccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Br)ccc21
Product: [Br-]
Yield: 61.2 %

Procedure:
3,5-dibromoisobenzofuran-1(3H)-one (94) (6.2 g, 21.24 mmol) and triphenylphosphine (5.57 g, 21.24 mmol) were heated at reflux in tetrahydrofuran (100 mL) overnight. The reaction was cooled and filtered to afford the desired material as a white solid (7.20 g, 71.5% yield); 1H NMR (400.132 MHz, CDCl3) δ 7.23 (1H, s), 7.59 (1H, d), 7.72-7.67 (7H, m), 7.92-7.84 (9H, m), 10.20 (1H, s);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20](O)=[O:21])[CH:13]1[CH2:15][CH2:14]1)(=[O:11])=[O:10].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH:55]1([N:58]2[CH2:63][CH2:62][N:61]([C:64]3([CH2:70][NH:71][C:72](=[O:79])[C:73]4[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=4)[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[CH2:60][CH2:59]2)[CH2:57][CH2:56]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20]([N:67]1[CH2:66][CH2:65][C:64]([CH2:70][NH:71][C:72](=[O:79])[C:73]2[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=2)([N:61]2[CH2:60][CH2:59][N:58]([CH:55]3[CH2:56][CH2:57]3)[CH2:63][CH2:62]2)[CH2:69][CH2:68]1)=[O:21])[CH:13]1[CH2:14][CH2:15]1)(=[O:10])=[O:11]
Reactant: O=C(NCC1(N2CCN(C3CC3)CC2)CCNCC1)c1ccncc1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(CNC(=O)c2ccncc2)(N2CCN(C3CC3)CC2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution of 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)-ethoxy)acetic acid AC8 (0.225 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resulting solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of N-((4-(4-cyclopropyl-piperazin-1-yl)piperidin-4-yl)methyl)isonicotinamide dihydrochloride AM12 (1.2 equiv.) in DMF (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 55%. MS, Rt=2.8 min, m/z=673.4 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[Br:19][C:20]1[S:24][C:23]([C:25](=[O:28])[CH2:26]Br)=[CH:22][CH:21]=1>CC(C)=O>[BrH:19].[NH2:1][CH:2]1[N:6]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[CH2:26][C:25](=[O:28])[C:23]1[S:24][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: Nc1nc2ccccc2n1CCN1CCOCC1
Reactant: O=C(CBr)c1ccc(Br)s1
Solvent: CC(C)=O
Product: Br
Product: NC1N(CCN2CCOCC2)c2ccccc2N1CC(=O)c1ccc(Br)s1
Yield: 88 %

Procedure:
Dissolve 2.46 g (10 mmol) of 2-amino-1-(2-morpholinoethyl)benzimidazole in 120 ml of acetone with heating. Subsequently, add 5-bromo-2-bromoacetylthiophene. After stirring, leave at room temperature for 3 to 4 hours. The 2-amino-3-(5-bromo-2-thenoylmethyl)-1-(2-morpholinoethyl)benzimidazole hydrobromide precipitate is filtered, washed twice with 20 ml of acetone each time and with ether (20 ml) to obtain 4.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[CH2:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:19]=[CH2:20]>C1(C)C=CC=CC=1>[C:21]1([CH2:18][CH:19]2[O:17][N:15]([CH3:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[CH2:20]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CCc1ccccc1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN1OC(Cc2ccccc2)CC1(Cn1ccnc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 7.04 g (0.0282 mol) of 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide (1: R1 =4-Cl) [prepared by reacting 2-(1H-imidazol-1-yl)-4'-chloroacetophenone (45.05 g, 0.204 mol), N-methylhydroxylamine hydrochloride (20.93 g, 0.251 mol), and sodium acetate (41.13 g, 0.502 mol) in 550 ml of ethanol] and 3.95 g (0.0334 mol) of allylbenzene (2: R2 =CH2C6H5) in 100 ml toluene is refluxed for 30 hours under a nitrogen atmosphere. Upon cooling to room temperature, the solvent is removed in vacuo. The resulting cis-/trans-diastereomeric mixture of compound 3 (R1 =4-Cl, R2 =CH2C6H5 is flash-chromatographed on neutral silica gel using a 98:2 by volume mixture of chloroform and methanol as eluent to give 3.80 g (36%) of isomer A. Following crystallization from ether a melting point of 118°-120° C. is determined.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:19](N=[N+]=[N-])=[O:20].C(OC(C)C)(C)C>C1C=CC=CC=1>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:19](=[O:20])[C:18]2[CH:17]=[C:16]([O:15][CH3:14])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: COc1cc(C(=O)N=[N+]=[N-])cc(OC)c1OC
Solvent: c1ccccc1
Solvent: CC(C)OC(C)C
Product: COc1cc(C(=O)NC2CCN(Cc3ccccc3)C2)cc(OC)c1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 1.8 g. (0.01 mole) of 3-amino-1-benzylpyrrolidine, 2.4 g. (0.01 mole) of 3,4,5-trimethoxybenzoyl azide, and 25 ml. of dry benzene was stirred 16 hours at room temperature followed by stirring for one hour at about 60°C. The mixture was cooled and 50 ml. of isopropyl ether added to the mixture. The crude crystalline product was separated by filtration and recrystallized from ethyl acetate-isopropyl ether mixture, giving 2.2 g. (60% yield). The melting point of the product after a second recrystallization from the same solvent was 128°-129°C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][CH2:38][C:24]=3[N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:26]=2[CH:27]=1>>[O:15]=[C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=2)[CH:14]=[CH:13][N:12]1[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39][CH2:38][C:24]=3[N:25]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=3)(=[O:30])=[O:29])[C:26]=2[CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 37.2 %

Procedure:
4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (131 mg, 0.545 mmol) and tert-butyl 7-bromo-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (255 mg, 0.505 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (125 mg, 34%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 9.01 (s, 1H), 8.29 (d, J=1.6 Hz, 1H), 8.08 (dd, J=8.3, 1.9 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.33 (dd, J=8.2, 1.6 Hz, 1H), 7.29-7.23 (m, 4H), 7.09 (dd, J=7.2, 1.8 Hz, 1H), 4.52 (s, 2H), 3.80-3.73 (br m, 2H), 3.18-3.09 (br m, 2H), 2.35 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][N:11]([CH3:30])[C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1.O>CS(C)=O>[CH3:9][O:10][N:11]([CH3:30])[C:12]([CH:13]1[CH2:2][CH:14]1[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)=[O:29]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)/C=C/c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CON(C)C(=O)C1CC1c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
660 mg (3.3 mmol) of trimethylsulphoxonium iodide and 3 ml of DMSO are introduced into a three-necked flask under a stream of nitrogen. 100 mg (4.12 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. A solution of 900 mg (3 mmol) of (E)-N-methoxy-N-methyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)acrylamide in 15 ml of DMSO is then added dropwise and the mixture is stirred at room temperature for two hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (80/20). After evaporating the solvents, 400 mg (43%) of N-methoxy-N-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropanecarboxamide are collected in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:14]C.[Br:16]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:16][C:4]1[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:14]
Reactant: BrBr
Reactant: COc1ccc(S(F)(F)(F)(F)F)cc1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
5.30 g of 2-chloro-1-methoxy-4-pentafluorosulfanylbenzene were dissolved in 150 ml of CHCl3 and admixed with 4.73 g of bromine and 638 mg of FeBr2. The mixture was stirred at RT for 18 hours, then admixed with a further 200 mg of FeBr2, stirred at RT for 6 hours and then admixed with a further 300 mg of FeBr2, stirred at RT for 2 hours and left to stand at RT for 18 hours. The reaction mixture was then poured onto 300 ml of a saturated aqueous Na2SO3 solution and extracted with 300 ml of CH2Cl2. The organic phase was then washed with 100 ml of water and dried over Na2SO4, and the solvent was removed under reduced pressure. 4.20 g of a colorless oil were obtained which was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.Cl[C:9]1[N:10]=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]2[N:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:16]=[CH:15][C:13]=2[N:14]=1>>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:9]2[N:10]=[C:11]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:12]3[N:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:3]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2nc(N3CCOCC3)c3nc(CN4CCC(C(C)(C)O)CC4)ccc3n2)n[nH]1

Procedure:
Following General Procedure C, 5-methyl-1H-pyrazol-3-amine and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 106. LCMS (MH+)=467.3. 1H-NMR (DMSO-d6): δ 11.8 (s, 1H), 8.91 (s, 1H), 7.78 (s, 1H), 7.62 (d, 1H), 6.48 (s, 1H), 4.39 (s, 4H), 3.99 (s, 1H), 3.76 (m, 4H), 3.59 (s, 2H), 2.90, (m, 2H), 2.19 (s, 3H), 1.93 (m, 2H), 1.63 (m, 2H), 1.24 (m, 2H), 1.16 (m, 1H), 1.03 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14]C)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:16](OC(=O)CC)(=O)[CH2:17][CH3:18].[NH4+:25].[OH-]>CCOCC.O>[CH2:17]([C:16]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=2)[CH:11]=[C:12]([OH:14])[N:25]=1)[CH3:18]
Reactant: [NH4+]
Reactant: CCC(=O)OC(=O)CC
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCc1nc(O)cc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
To a solution of methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 (10.01 g, 47.6 mmol) in propionic anhydride (24.0 mL, 187.2 mmol) at 0° C. in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added HClO4 (ca. 70% solution in water, 4.89 mL, 56.6 mmol) over a period of 30 min. The reaction mixture was then allowed to warm up to RT, stirred for 45 min and diluted with Et2O (450 mL). The solid was filtered and washed several times with Et2O giving 10.5 g of a brown solid. To a suspension of this solid (9.98 g, 29.8 mmol) in H2O (54 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer and cooled in an ice bath was added dropwise concentrated NH4OH (81 mL). After complete addition, the ice bath was removed and the reaction mixture was stirred at RT for 1 h, after which the solid was filtered and washed with plenty of water until neutral pH of the filtrate. The solid was dried under vacuum in presence of P2O5 to give 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 as a yellow solid (5.30 g, 48% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[Se](=O)=[O:28]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[O:28])[O:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=[Se]=O
Reactant: Cc1cc(=O)c(-c2ccc(F)cc2F)c(-c2ccc(S(C)(=O)=O)cc2)o1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2oc(C=O)cc(=O)c2-c2ccc(F)cc2F)cc1
Temperature: 180 °C
Yield: 48.4 %

Procedure:
To a solution of 3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one (1.7 g; 4.5 mmoles) (compound 13) in dioxane (45 ml), selenium dioxide (2.2 g, 20 mmoles) was added and the mixture heated in a pressure vessel at 180° C. for 1 hour. After cooling, the reaction mixture was filtered, the solvent removed under reduced pressure and the residual oil purified by column chromatography with silica gel and ethyl acetate as eluent. 5-(2,4difluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-4H-pyran-2-carbaldehyde (0.85 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(Cl)CCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]12[CH2:7][CH2:6][CH:5]([CH2:4][C:3]1=[O:20])[C:8]([CH3:10])([CH3:9])[O:11]2
Reactant: CC1=CC[C@@H](C(C)(C)O)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC12CCC(CC1=O)C(C)(C)O2
Temperature: 25 °C

Procedure:
A mixture of 3.08 g. (0.02 mole) α-terpineol and 4.45 g. (0.022 mole) of 85 percent m-chloroperbenzoic acid in 70 ml. of ethylene dichloride is refluxed under nitrogen for 20 hours, then cooled to room temperature and washed with aqueous sodium bisulfite and sodium bicarbonate solutions. The solvent is removed in vacuo and the resulting oil is treated in situ with 2.94 g. (0.0136 mole) pyridinium chlorochromate. The resulting mixture is stirred under nitrogen in 35 ml. of methylene chloride at ambient temperatures for 2.5 hours. After addition of 200 ml. diethyl ether, the mixture is filtered through celite and the solvent evaporated to give, on steam distillation, 1,3,3-trimethyl-2-oxabicyclo [2,2,2]octan-6-one; m.p. 50° to 52° C.
Reaction SMILES: C[Si](C)(C)[O-:3].[Na+].[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10](F)[CH:9]=1>C1COCC1>[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10]([OH:3])[CH:9]=1
Reactant: C[Si](C)(C)[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(Br)cc1O
Temperature: 25 °C
Yield: 205.8 %

Procedure:
A solution of 2 M sodium trimethylsilanolate (15.6, 31.1 mmol) in THF was added dropwise to 4-bromo-2,5-difluoronitrobenzene (2.47 g, 10.4 mmol) under a nitrogen atmosphere. A bright red suspension was formed, and the mixture was refluxed for 27 hours. The mixture was cooled to room temperature and concentrated. Water (6 mL) was added, and the solution was acidified with a 10% HCl solution, extracted with DCM (70 mL×2). The organic layers were combined and concentrated to give 5-bromo-4-fluoro-2-nitrophenol (5.05 g, 2.06%). MS m/z: 236 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 7.48 (d, J=5.87 Hz, 1H), 7.95 (d, J=8.41 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[C:5]2[CH:13]=[C:14]([Cl:23])[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:4]=2[O:3]1.Cl>C(O)(=O)C.O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5]2[CH:13]=[C:14]([Cl:23])[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:4]=2[O:3]1
Reactant: CCOC(=O)Cn1c(=O)oc2cc(-c3ccccc3)c(Cl)cc21
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cn1c(=O)oc2cc(-c3ccccc3)c(Cl)cc21
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-oxo-5-chloro-6-phenyl-3-benzoxazolineacetate (1.5 g) in acetic acid (10 ml) was added conc.hydrochloric acid (5 ml). The reaction mixture was stirred at 60° C. for 1.5 hours and then cooled to ambient temperature. The resultant mixture was diluted with water to precipitate crystals, which were separated by filtration, washed with water, dried and then recrystallized from a mixture of chloroform and acetone to give 2-oxo-5-chloro-6-phenyl-3-benzoxazolineacetic acid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([N:19](CC)[CH:20]([CH3:22])[CH3:21])(C)C.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:28]([C:27]3[CH:31]=[CH:21][C:20]([NH:19][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=4[Cl:25])=[CH:22][C:26]=3[Cl:25])=[O:29])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.50 g of 5-2-chloro-4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.28 g of N,N-diisopropylethylamine and 0.45 g of 2,4-dichlorobenzoyl chloride in 25 ml of methylene chloride is stirred at: room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give the desired product as a solid residue, m.p., 150°-165° C.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[F:8][C:9]([F:26])([F:25])[O:10][CH:11]([F:24])[C:12]([F:23])([F:22])[O:13]NCC1C=CC=CC=1.[Cl:27][C:28]1[C:29]([CH2:37][CH3:38])=[N:30][N:31]([CH3:36])[C:32]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[F:26][C:9]([F:8])([F:25])[O:10][CH:11]([F:24])[C:12]([F:22])([F:23])[O:13][C:28]1[CH:29]=[CH:37][C:7]([CH2:6][NH:3][C:33]([C:32]2[N:31]([CH3:36])[N:30]=[C:29]([CH2:37][CH3:38])[C:28]=2[Cl:27])=[O:34])=[CH:33][CH:32]=1
Reactant: CCc1nn(C)c(C(=O)Cl)c1Cl
Reactant: FC(OC(F)(F)F)C(F)(F)ONCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nn(C)c(C(=O)NCc2ccc(OC(F)(F)C(F)OC(F)(F)F)cc2)c1Cl
Temperature: 25 °C

Procedure:
A mixture consisting of 4 ml of methylene chloride, 0.22 ml of triethylamine and 450 mg of 4-((2-trifluoromethoxy-1,1,2-trifluoroethoxy)-benzylamine (1.56 moles) is slowly added dropwise to a solution of 332 mg (1.6 mmoles) of 4-chloro-3-ethyl-1-methyl-5-pyrazolecarboxylic acid chloride in 6 ml of methylene chloride. The solution obtained is maintained under agitation at ambient temperature for 4 hours.