Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Br[C:43]1[CH:44]=[CH:45][C:46](=[O:53])[N:47]([CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:48]=1>CN(C)C=O>[CH:50]1([CH2:49][N:47]2[C:46](=[O:53])[CH:45]=[CH:44][C:43]([C:22]3[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]4[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:40])[CH3:41])([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:15][C:14]4=[O:16])[CH3:18])=[CH:24][CH:23]=3)=[CH:48]2)[CH2:52][CH2:51]1
Reactant: O=c1ccc(Br)cn1CC1CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC3CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.84 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.40 g) and 5-bromo-1-cyclopropylmethyl-1H-pyridin-2-one (0.24 g) in dimethyl-formamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (34 mg) was added. The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1->95:5) to afford the title compound that was crystallized with little ethyl acetate. Yield: 0.19 g (46% of theory); Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.ClC1C=CC(S)=CC=1.ClC1C=CC=CC=1C#[N:29]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([S:12][C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]#[N:29])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1Cl
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Agent: Sc1ccc(Cl)cc1
Product: N#Cc1ccccc1Sc1ccc(Cl)cc1

Procedure:
Method of preparing 2-chloro-thioxanthone which comprises reacting an alkali metal derivative of 4-chloro-thiophenol with 2-chloro-benzonitrile in an organic solvent to form 2-(4'-chloro-phenylthio)-benzonitrile, hydrolyzing said 2-(4'-chloro-phenylthio)-benzonitrile to form 2-(4'l -chloro-phenylthio)-benzoic acid and cyclising said 2-(4'-chloro-phenylthio)-benzoic acid by dehydration to produce 2-cloro-thioxanthone.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[CH3:39][C:40]1[O:44][C:43]([CH2:45][NH2:46])=[N:42][N:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:46][CH2:45][C:43]1[O:44][C:40]([CH3:39])=[N:41][N:42]=1)=[O:4]
Reactant: Cc1nnc(CN)o1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)o1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), (5-methyl-1,3,4-oxadiazol-2-yl)methanamine (16.52 mg, 0.146 mmol), and BOP (64.6 mg, 0.146 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.5 min) to give single enantiomer 2-hydroxy-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15.1 mg, 0.027 mmol, 33.7% yield): LCMS=527.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.24 (2 H, m), 7.66-7.78 (4 H, m), 7.54-7.66 (3 H, m), 5.21 (1 H, s), 4.63 (2 H, d, J=3.30 Hz), 2.49 (3 H, s). HPLC Peak RT=9.2 min (Analytical Method C).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[NH:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[NH:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[CH:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Cl
Temperature: 0 °C
Yield: 32.9 %

Procedure:
A solution of triphenylphosphine (118 mg, 0.45 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (91 mg, 0.51 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 16, 100 mg, 0.30 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzimidazole (60 mg, 0.45 mmol) and pyridine (0.073 mL, 0.91 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-(1H-benzoimidazol-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (44 mg, 33%) as a cream colored solid: EI-HRMS m/e calcd for C22H24CIN3O3S (M+) 445.1227, found 445.1213.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-Amino-4,6-dichloropyrimidine (1.0 g, 6.1 mmol, Alfa Aesar, Cat. No. A11330), 1-methyl piperazine (0.74 mL, 6.7 mmol, Aldrich, Cat. No. 130001), and N,N-diisopropylethylamine (1.3 mL, 7.3 mmol) in isopropyl alcohol (5 mL) was heated at 110° C. for 2 hours. The reaction mixture was cooled to room temperature (r.t.). The precipitate formed was filtered and then washed by a small amount of isopropanol. The precipitate collected was dried under vacuum to afford this compound and used in the next step without further purification. LCMS(M+H)+: m/z=228.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:47][C:48]1[CH:49]=[CH:50][C:51]([CH3:77])=[C:52]([CH:76]=1)[C:53]([NH:55][C:56]1[CH:57]=[N:58][C:59]([NH:62][C:63]2[CH:68]=[CH:67][C:66]([N:69]3[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]3)=[CH:65][CH:64]=2)=[N:60][CH:61]=1)=[O:54]>CN(C=O)C.CO.CS(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:47][C:48]1[CH:49]=[CH:50][C:51]([CH3:77])=[C:52]([C:53](=[O:54])[NH:55][C:56]2[CH:57]=[N:58][C:59]([NH:62][C:63]3[CH:64]=[CH:65][C:66]([N:69]4[CH2:70][CH2:71][N:72]([CH3:75])[CH2:73][CH2:74]4)=[CH:67][CH:68]=3)=[N:60][CH:61]=2)[CH:76]=1)=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc3ccccc3n2C)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 16×120 mm resealable pyrex tube, 1-methyl-1H-indole-2-carboxylic acid (0.11 g, 0.62 mmol), HATU (0.24 g, 0.62 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.17 ml, 0.96 mmol) were taken up in DMF (5 mL) and allowed to stir at rt for 30 min. 5-amino-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)benzamide 30 (0.200 g, 0.48 mmol) was added and the mixture was stirred at rt overnight. The crude reaction mixture was taken up in minimal MeOH/DMSO and purified by preparative HPLC (acidic Shimadzu: 15-85% (0.1% TFA in CH3CN) in H2O over 20 min). Clean fractions were combined and neutralized with saturated NaHCO3 then extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated to afford 1-methyl-N-(4-methyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenyl)-1H-indole-2-carboxamide 31 as a tan solid. MS m/z found 575.2 [MH+]; calc. for C33H34N8O2=574.28.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([F:32])[CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:32][C:21]1[CH:20]=[C:19]([NH:18][CH2:15][C:11]2[CH:10]=[C:9]([C:5]3[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]=3[CH3:17])[CH:14]=[CH:13][CH:12]=2)[CH:24]=[CH:23][C:22]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (1.05 g, 4.64 mmol), ethyl 3-(4-amino-2-fluorophenyl)propanoate. (1.00 g, 4.73 mol), acetic acid (0.80 mL, 14 mmol) and 1,2-dichloroethane (20 mL) was stirred at room temperature for 2 hr, and sodium triacetoxyborohydride (3.00 g, 14.2 mmol) was added. The mixture was stirred overnight at room temperature and concentrated. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title compound (1.29 g, yield 66%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].Cl.[CH2:31]([O:38][CH2:39][CH2:40][CH:41]([NH:43][CH:44]([CH3:46])[CH3:45])[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][CH2:39][CH2:40][CH:41]([N:43]([CH:44]([CH3:46])[CH3:45])[C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:25][CH:24]=1)[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)Cl)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)NC(C)CCOCc1ccccc1
Agent: Cl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoyl chloride and rac-N-(3-benzyloxy-1-methyl-propyl)-N-isopropyl-amine hydrochloride as described for example 9.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][S:26]4(=[O:33])=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: O=S1(=O)CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 87.5 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (429 mg) described in Preparation Example 111 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (425 mg) was obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)=O.B(F)(F)[F:26].CCOCC.C(ON=O)(C)(C)C>COCCOC.CCOCC>[F:26][C:2]1[CH:3]=[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCOc1cc(N)cc(C(=O)OC)c1OCCOC
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Agent: O=C=O
Solvent: CCOCC
Solvent: COCCOC
Product: COCCOc1cc(F)cc(C(=O)OC)c1OCCOC
Temperature: 110 °C
Yield: 16.2 %

Procedure:
A solution of methyl 5-amino-2,3-bis{[2-(methyloxy)ethyl]oxy}benzoate (2.2 g, 7.4 mmol) in 1,2-dimethoxyethane (5 mL) was cooled at −4° C. and then cooled in solid dry-ice. To this mixture was added first boron trifluoride diethyl etherate (1.3 mL, 10 mmol), and then tert-butylnitrite (1.4 mL, 12 mmol), and the resulting mixture was stirred at −4° C. for 2 hours. It was then diluted with ether (100 mL) and a solid precipitated and was collected and washed with ether. The solid was suspended in 1,2,4-trichlorobenzene (20 mL) and heated at 110° C. for 18 hours. After cooling to room temperature, it was applied directly onto a silica gel column with hexane, and then chromatographed (30% ethyl acetate-hexane) to give methyl 5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}benzoate (0.35 g, 1.2 mmol, 16% yield). 1H NMR (400 MHz, CDCl3): 7.05-7.02 (d, d, 1H), 6.83-6.80 (d, d, 1H), 4.20-4.13 (m, 4H), 3.90 (s, 3H), 3.79-3.72 (m, 4H), 3.44 (s, 6H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].O[CH2:13][CH:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)C>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:21][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:4]1
Reactant: OCC(O)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCO
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3)O2)cc1

Procedure:
A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 8.4 parts of α-(hydroxymethyl)benzylalcohol, 0.1 parts of p-toluene sulfonic acid, 210 parts of benzene and 40 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is triturated in methanol. The product is filtered off and crystallized from methanol, yielding 2-(bromomethyl)-2-(p-chlorophenyl)-4-phenyl-1,3-dioxolane; mp. 60° C.
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)[CH:14]=[N:13][C:12]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>[Pd].CO>[CH3:22][C:18]1[CH:17]=[C:16]([N:15]2[C:11]3([CH2:24][CH2:25][NH:8][CH2:9][CH2:10]3)[C:12](=[O:23])[NH:13][CH2:14]2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(N2C=NC(=O)C23CCN(Cc2ccccc2)CC3)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cccc(N2CNC(=O)C23CCNCC3)c1
Reaction time: 24 h

Procedure:
A mixture of 8-benzyl-1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (1.64 g, 4.9 mmol) and 10% palladium on charcoal (0.8 g) in a mixture of methanol (100 mL) and methanol saturated with anhydrous hydrochloride gas (5 mL) was shaken in a Parr hydrogenator at 55 psi for 24 h. The resultant mixture was filtered through a plug of Celite, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of 10% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:17]=[CH:18][C:19]4[C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:22]([CH2:30][CH3:31])[C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(=O)C>Cl.C(O)(=O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:17]=[CH:18][C:19]4[C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:22]([CH2:30][CH3:31])[C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[CH:32][CH:33]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc(NC(C)=O)cc4)CC3)nc21
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc(N)cc4)CC3)nc21
Temperature: 90 °C
Yield: 77.9 %

Procedure:
A solution of 32.0 g of 2-[4-(p-acetamidobenzyl)-1-piperazinyl]-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in a mixture of 580 ml of 13% hydrochloric acid and 140 ml of 50% acetic acid was heated at 90° C. for 70 minutes with stirring and concentrated to dryness under reduced pressure. The residue was dissolved in 200 ml of water, the solution made alkaline with 20 ml of a 50% sodium hydroxide solution, and adjusted to pH 7.5 with acetic acid. The crystalline precipitate was collected and recrystallized from ethanol to give the product (22.6 g), m.p. 198°-201° C.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:10])[O:6][C:7]=1[CH2:8][Br:9].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][CH2:8][C:7]1[O:6][C:5](=[O:10])[O:4][C:3]=1[CH2:2][O:19][C:17](=[O:18])[CH2:16][O:15][CH2:14][CH2:13][O:12][CH3:11]
Reactant: O=c1oc(CBr)c(CBr)o1
Reactant: COCCOCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOCC(=O)OCc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
4,5-Dibromomethyl-2-oxo-1,3-dioxolene (136 mg, 0.50 mmol) was dissolved in acetonitrile (5.0 mL). Thereto were added 2-methoxyethoxyacetic acid (0.057 mL, 0.50 mmol) and potassium carbonate (69 mg, 0.50 mmol) This mixture was stirred at 25° C. for 30 minutes. After the ordinary post-treatment, the reaction product was purified by thin-layer chromatography (developed with chloroform) to obtain Compound S-32 (45 mg, yield 28%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:9]([CH3:24])([CH3:23])[CH2:8]2)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=1)[C:9]([CH3:24])([CH3:23])[CH2:8]2)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Cl)c2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)c2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-8-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.2 g, 2.94 mmol), morpholine (1.3 mL, 14.7 mmol), copper(I) iodide (140 mg, 0.7 mmol), N,N-dimethylglycine hydrochloride (206 mg, 1.5 mmol) and potassium carbonate (1.2 g, 8.8 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (973 mg, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27ClN2O3 (M+H)+: 415.94, observed: 415.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]([NH:41][CH3:42])([CH3:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]([CH:38]([CH3:40])[CH3:39])[CH3:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CNC(C)C
Product: CC(C)N(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-isopropylmethylamine according to conditions described in general procedure C. Mp: 94-96° C.; 1H NMR (400 MHz, CDCl3) δ 1.06-1.14 (m, 6 H), 2.84 (s, 3 H), 3.25 (t, J=4.0 Hz, 4 H), 3.87 (t, J=4.8 Hz, 4H), 5.95 (d, J=5.2 Hz, 1 H), 6.78 (d, J=11.2 Hz, 1 H), 7.07 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1 H), 7.49-7.59 (m, 3 H), 7.89 (d, J=8.8 Hz, 1 H), 7.96 (d, J=7.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1 H), 8.14-8.17 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[F:13][C:14]([F:31])([F:30])[C:15]1[CH:16]=[C:17](/[CH:21]=[N:22]/[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[S:3]([CH2:6][CH:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:31])([F:30])[F:13])[CH:16]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)/N=C/c1cccc(C(F)(F)F)c1
Reactant: CN(C)S(C)(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)CC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 676 mg (5.49 mmol) of N,N-dimethylmethanesulphonamide in 10 ml of THF was admixed slowly at −78° C. with 3.43 ml (5.49 mmol) of 1.6M n-butyllithium solution in hexane versetzt. After 30 min at −78° C., the colourless solution obtained was added to a solution, cooled to −78° C. beforehand, of 500 mg (1.83 mmol) of the compound from Example 11A in 10 ml of THF. The reaction mixture was stirred at −78° C. for 30 min more and then slowly warmed to RT. After 30 min it was cooled to −20° C. again and the reaction was halted by addition of 5 ml of 10% strength aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate and then washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC [Method 23]. The product fraction was freed from the solvent on a rotary evaporator. Drying of the residue in an HV gave 296 mg (41% of theory) of the title compound.