Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:10]([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:29](Br)[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH2:33]([O:32][C:30]([CH:29]1[O:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:8][CH3:9])[CH3:20])=[CH:13][C:14]=2[O:19]1)=[O:31])[CH3:34]
Reactant: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(CC(C)N(CC)C(=O)OC(C)(C)C)cc2O1
Temperature: 120 °C
Yield: 79.1 %

Procedure:
To 2 g (6.7 mmol) of 2C was added 40 mL of anhydrous DMF followed by 3.5 g (25 mmol) of anhydrous K2CO3, 5 g of 3 A° molecular sieves and 3.2 mL (25 mmol) of ethyl dibromoacetate. The reaction mixture was heated at 120° C. for 3 hours under argon atmosphere and then concentrated under reduced pressure. To the residue 75 mL of ethyl acetate were added and filtered. To the filtrate 75 mL of water were added and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with 5×75 mL of ethyl acetate. All the organic layers were combined, dried (anhydrous Na2SO4), and concentrated to dryness. The residue was purified by silica gel column chromatography using 10% ethyl acetate in hexane to give 954 mg (5.3 mmol, 37%) of 2D as a colorless gum (M+Na, 402).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:36]=[N:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:36]=[N:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1cnc2ccccc2n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cnc2ccccc2n1
Reaction time: 2 h
Yield: 17.1 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and 2-hydrazinylquinoxaline (0.14 g, 1.2 eq.) in EtOAc. T3P (50% in EtOAc; 0.83 mL, 2.0 eq.) and DIPEA (0.5 mL, 4.0 eq.) were added under nitrogen atmosphere at −55 to −60° C. and the reaction mixture was stirred for 2 hr before being concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.150 g of crude solid. Purification using Combi-Flash column chromatography (eluting with MeOH:CH2Cl2; desired compound started eluting at 5% MeOH in CH2Cl2) afforded 60 mg (yield: 20%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(quinoxalin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ=10.851 (s, 1H), 9.89-9.87 (s, 1H), 9.67 (s, 1H), 8.49-8.54 (m, 3H), 8.26 (s, 1H), 8.28 (s, 1H), 7.86-7.88 (d, J=8 Hz, 1H), 7.45-7.66 (m, 4H), 6.17-6.20 (d, J=10.4 Hz, 1H); LCMS for C21H14F6N7O [M+H]+ 494.37. found 494.19 (RT 2.88 min, purity: 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].I[CH:13]1[C:18](OC)([O:19]C)[CH2:17][CH2:16][O:15][CH2:14]1>>[O:19]=[C:18]1[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: COC1(OC)CCOCC1I
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(C2COCCC2=O)cc1

Procedure:
4-cyanophenylboronic acid was reacted as described in Intermediate X(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) to give 4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile (Intermediate AA(2)). LC-MS (M+H)+=202.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.66 (d, J=8.24 Hz, 2H) 7.38 (d, J=8.55 Hz, 2H) 4.23-4.31 (m, 2H) 3.94-4.02 (m, 2H) 3.85-3.92 (m, 1H) 2.55-2.65 (m, 1H) 2.52 (t, J=5.80 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1.C[O:27]C1C=CC(N2[C@@H](C)[C@@H](COC3C=CC(C#N)=CC=3)OC2=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C[C@@](C)(COc3ccc(C#N)cc3)OC2=O)cc1
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Product: COc1ccc(N2C[C@@](C)(COc3ccc(C=O)cc3)OC2=O)cc1
Yield: 85 %

Procedure:
The same procedure of Example 16 was repeated except that 4-[(S)-(+)-3-(4-methoxyphenyl)-5-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile obtained in Reference Example 16 was used in lieu of 4-[(4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile to give the title compound (compound 49) as an oil (yield 85%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3][CH:2]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[N:1]1[CH:6]=[C:5]([CH2:7][O:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH:4]=[N:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cncnc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cncnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a mixture of pyrimidin-5-yl-methanol, DMAP and NEt3 was slowly added MsCl at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was extracted with water and dichloromethane. The organic phase was dried on Na2SO4, filtered and the solvent was evaporated. Silica gel column chromatography (Ethyl acetate/hexane 1:1) gave the title compound in 40% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]([C:22]([CH3:24])=[O:23])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:10])([O-:3])=[O:2].[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:29].N1CCCCC1>C(O)C>[NH2:29][C:28]1[O:23][C:22]([CH3:24])=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:10])[CH:7]([C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CC#N
Reactant: CCCCCCCCCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCCCCCOC(=O)C1=C(C)OC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 5.7 g (15 mmol) of decyl 2-(3-nitrobenzylidene)acetoacetate and 1.8 g (15 mmol) of ethyl cyanoacetate in 15 ml of ethanol was heated to boiling in the presence of 0.3 ml of piperidine, for 4 hours. The solvent was then removed by distillation and the oily residue was purified by column chromatography (SiO2, chloroform) and brought to crystalli ation, melting point: 100° C., yield: 3.3 g (45%).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Cl:7][C:8]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>>[Cl:7][C:8]1[CH:15]=[C:14]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: OCCCCO
Product: N#Cc1ccc(OCCCCO)cc1Cl
Yield: 4.4 %

Procedure:
Following the procedure described for Example 29, 1,4-butanediol (1 mL, 10 mmol) was reacted with 2-chloro-4-fluoro-benzonitrile (159 mg, 1.0 mmol) for 24 hours at room temperature. Purification by reverse phase high pressure chromatography eluting with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) provided 10 mg of 2-chloro-4-(4-hydroxy-butoxy)-benzonitrile. 1H NMR (CDCl3) δ 7.54 (d, 1H), 6.98 (d, 1H), 6.83 (dd, 1H), 4.03 (t, 2H), 3.71 (t, 2H), 1.90 (m, 2H), 1.72 (m, 2H); MS 226.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: Brc1ccccc1O[C@@H]1CCCNC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3O[C@@H]3CCCNC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (R)-3-(2-bromophenoxy)piperidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48-8.45 (m, 2H), 7.60-7.48 (m, 2H), 7.46-7.34 (m, 3H), 7.23 (d, J=8.0, 1H), 7.13-7.06 (m, 1H), 6.87 (s, 2H), 4.68-4.56 (m, 1H), 3.35-3.30 (m, 1H), 3.11-2.99 (m, 2H), 2.98-2.89 (m, 1H), 2.03-1.93 (m, 1H), 1.88-1.77 (m, 1H), 1.72-1.58 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C:11]=1[C:20]([O:22][CH3:23])=[O:21].[Mg]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH:11]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(c2cc(F)c(F)cc2F)CCC2(C1)OCCO2
Agent: [Mg]
Solvent: CO
Product: COC(=O)C1CC2(CCC1c1cc(F)c(F)cc1F)OCCO2

Procedure:
To a stirred solution of methyl 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate (1.93 g, 5.9 mmol) in methanol (50 mL) was added magnesium (1.43 g, 59 mmol), and the mixture was refluxed overnight under nitrogen atmosphere. The white precipitate that formed was filtered over Celite, and the filtrate was evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:33]4[CH2:32][CH2:31][NH:30][CH:29]([C:25]5[S:24][CH:28]=[CH:27][CH:26]=5)[CH2:34]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: c1csc(C2CNCCN2)c1
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5cccs5)C4)c(F)cc3cc2c1=O
Yield: 96.5 %

Procedure:
(RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.59 g) and (RS)-2-(2-thienyl)piperazine (1.02 g). (RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-8-[3-(2-thienyl)-1-piperazinyl ]-1,4-dihydrobenzo[b][1,8]naphthyridine (2.25 g) is obtained in the form of a yellow solid, m.p. 228° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH2:21])[CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)=[CH:26][C:25]=1[C:40](Cl)=[O:41].C(N(CC)CC)C>>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C@@H:17]([NH:21][C:40]([C:25]3[CH:26]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=4)[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[O:41])[CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: COCC(N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC[C@@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1OC
Yield: 78.7 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-methoxymethyl-ethyl]-amide (45 mg) was prepared from 1-(3′-Chloro-4′-fluoro-biphenyl-4-ylmethyl)-2-methoxy-ethylamine hydrochloride salt (35 mg, 0.1 mmol) and 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl chloride (32 mg, 0.1 mmol) in presence of triethyl amine (41 mg, 0.41 mmol) according to the general procedure M.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[N:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=1)=[O:6])[CH3:3].Cl.[NH2:25][OH:26].N1CCCCC1>CS(C)=O>[CH3:21][C:19]([CH3:22])([O:18][C:16]([N:7]([C:5]([O:4][C:2]([CH3:23])([CH3:3])[CH3:1])=[O:6])[C:8]1[N:9]=[CH:10][C:11]([C:14](=[NH:15])[NH:25][OH:26])=[N:12][CH:13]=1)=[O:17])[CH3:20]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C#N)cn1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(C(=N)NO)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 55.2 %

Procedure:
A solution of 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-2-pyrazinecarbonitrile (305.7 mg, 0.954 mmol) in dimethyl sulfoxide (5.8 mL) was treated with hydroxylamine hydrochloride (333.8 mg, 4.804 mmol) and piperidine (0.50 mL, 5.050 mmol). The reaction was stirred at 25° C. for 50 min and then was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/3 ethyl acetate/hexanes) afforded the 5-[[bis[(1,1-dimethylethoxy)carbonyl]]amino]-N-hydroxy-2-pyrazinecarboximidamide as a white solid (186.2 mg, 55%): mp 185–186° C.; (ES)+-HRMS m/e calcd for C15H23N5O5 (M+H)+ 354.1772, found 354.1775.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH:32]3[CH2:34][CH2:33]3)[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]3[CH:23]=[C:24]4[N:31]([CH:32]5[CH2:34][CH2:33]5)[CH2:30][CH2:29][N:25]4[C:26](=[O:28])[N:27]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc2n1CCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol and 7-chloro-1-cyclopropyl-2,3-dihydroimi-dazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH2:14]([CH:17]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:29])[CH:15]=[CH2:16].CC(C)=O>C(O)(C)C>[CH2:14]([CH:17]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:29])[CH:15]=[CH2:16]
Reactant: C=CCC1CCCCCCCCCCC1=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C=CCC1CCCCCCCCCCC1O
Yield: 95 %

Procedure:
0.1 mole of aluminum isopropoxide in 500 ml of isopropanol is placed in a three-necked flask provided with a stirrer and a Vigreux column. The mixture is refluxed. A 25% by weight solution of 2-(2-propenyl)-cyclododecanone in isopropanol is added dropwise to the boiling reaction mixture, over a period of 12 hours. The acetone produced, which serves at the same time as indicator for the progress of the reaction, is collected at the top of the column. After approximately a further hour of refluxing, the reaction is complete. After the isopropanol has been drawn off, the reaction mixture is hydrolyzed with 6N hydrochloric acid. Extraction is then carried out with 200 ml of toluene and the organic phase is worked up by distillation. Finally, 2-(2-propenyl)-cyclododecanol is obtained as a colorless liquid in a yield of 95% of the theoretical yield at a boiling range of from 172° to 175° C. at 12 torr.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1NCC(O)COC1C=CC(C)=CC=1C)[NH:6]2.[CH3:44][CH:45]([NH2:52])[CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1.CCN(CC)CC>CCO>[Cl:1][C:2]1[C:13]2[C:12](=[O:14])[N:11]([CH:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[C:10](=[O:22])[C:9]=2[CH:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=1[NH:52][CH:45]([CH3:44])[CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1)[NH:6]2
Reactant: CC(N)Cc1cccs1
Reactant: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3c(Cl)c4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4=O)c(C)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2c(Cl)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O

Procedure:
4-Chloro-2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (18 mg, 0.04 mmol), 1-methyl-2-thiophen-2-yl-ethylamine (8.5 mg, 0.06 mmol) and Et3N (0.2 mL, 1.43 mmol) in EtOH (1.0 mL) was heated at 80° C. for 17 h and then concentrated to result a residue which was subjected to HPLC purification to furnish the title compound in TFA salt form (6.73 mg, 25%). 1H NMR (DMSO-d6) δ 1.36 (d, J=6 Hz, 3H, CH3), 1.95 (m, 2H), 2.52 (m, 2H), 2.74 (s, 3H, CH3), 3.02-3.22 (4H), 3.45 (m, 2H), 4.08 (m, 1H), 4.28 (m, 1H), 6.19 (d, J=8 Hz, 1H), 6.89 (m, 1H), 7.00 (m, 1H), 7.29 (m, 1H), 7.39 (m, 1H), 8.09 (s, 1H), 11.01 (d, J=8 Hz, 1H), 11.35 (d, J=6 Hz, 1H); ESI-MS m/z 551.3 (MH+).
Reaction SMILES: ClC1C=CC([C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18]([OH:20])=[O:19])=[CH:14][C:13]([F:21])=[CH:12][CH:11]=3)=[O:7])=CC=1.Br[C:25]1[CH:26]=[C:27]([Cl:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][C:18]([OH:20])=[O:19])=[CH:14][C:13]([F:21])=[CH:12][CH:11]=2)=[O:7]
Reactant: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2ccc(F)cc12
Reactant: Clc1cccc(Br)c1
Product: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(F)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 5-fluoro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 21, step 1) and 3-bromochlorobenzene.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][C@H:16]1[CH2:21][O:20][CH2:19][C@H:18]([CH3:22])[NH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:15][C@@H:16]1[N:17]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:18]([CH3:22])[CH2:19][O:20][CH2:21]1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C[C@H]1COC[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)COC[C@@H]3C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.6 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (620 mg, 2.96 mmol) and (3S,5S)-3,5-dimethylmorpholine (341 mg, 2.96 mmol) and potassium carbonate (1.0 g, 7.4 mmol), in DMF (15 mL), was stirred in a 35° C. oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Methyl 2-((3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil. 1H NMR consistent.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][CH:33]([NH2:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:38][CH:33]([CH3:32])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:30])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: CC(NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 68 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 19 h at 75° C. under nitrogen. The reaction mixture was concentrated and the residue dissolved in DCM, washed twice with 1N aqueous HCl and once with water. The organic phase was dried (sodium sulfate) and concentrated. The residue was crystallised from ethyl acetate/heptane 1:3 to give 225 mg (68%) of the title compound. Mp 155.5-158.5° C. 1H NMR (300 MHz, CDCl3): δ=0.9 (s, 9H), 1.0 (d, 3H), 3.0 (m, 1H), 7.40 (s, 2H), 7.50 (d, 2H), (s, 1H), 7.82 (d, 2H); MA calc for C23H22ClF6N3O2S: C, 49.87%; H, 4.00%; N, 7.59%. Found: C, 49.86%; H, 4.29%; N, 7.55%.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)N2CCOCC2)c1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (2.19 g, 10.18 mmol) in THF (20.37 mL) was treated with N,N′-carbonyldiimidazole (1.98 g, 12.2 mmol). The reaction mixture was stirred at ambient temperature overnight (14 h). Morpholine (3.11 mL, 35.6 mmol) was added in one portion. The resulting solution was stirred for 8 h and then partitioned between EtOAc and water. Organic layer washed with water, dilute HCl, saturated aqueous Na2CO3, water and brine. The solution was then concentrated in vacuo to afford (2-bromo-3-methylphenyl)(morpholino)methanone as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][NH:4][C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:4]([C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][C:2]([F:18])([F:19])[F:1])=[O:24]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NCC(F)(F)F)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](N(CC(F)(F)F)C(=O)c1ccccc1Cl)CC2
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 3-(2,2,2-trifluoroethylamino)-2,3-dihydro-1H-indene-5-carboxylate (A-18) (870 mg, 3.18 mmol, 1.0 eq.) in methylene chloride (12 ml) was added TEA (1.1 ml, 7.95 mmol, 2.5 eq.) and the reaction mixture was allowed to stir for 15 min. 2-Chlorobenzoyl chloride (0.44 ml, 3.50 mmol, 1.1 eq) was added to the reaction mixture and it was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the mixture was diluted with methylene chloride (50 ml) and the organic layer was washed with water (20 ml) and brine (20 ml), and dried over anhydrous Na2SO4. The solvent was evaporated to afford the crude product which was purified by column chromatography (silica gel; 7% ethyl acetate/hexanes) to yield the desired compounds as a colourless gummy solid. Yield: 85% (1.1 g, 2.67 mmol).