Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>C1COCC1>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:31][CH:30]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCOCC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (prepared below, 50 mg, 0.155 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (30.4 mg, 0.170 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 41% (31 mg, 0.075 mmol) of the title compound.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:23])[CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([CH2:30][C:31](O)=[O:32])[N:28]=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1>>[CH3:24][C:25]1[N:29]([CH2:30][C:31]([N:20]2[CH2:19][CH2:18][CH:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:11][CH2:10][CH2:9][CH:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:23])[N:13]=3)[CH2:22][CH2:21]2)=[O:32])[N:28]=[C:27]([C:34]([F:36])([F:35])[F:37])[CH:26]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC(CCCc1csc(C2CCNCC2)n1)c1ccccc1
Agent: Cl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(CCCC(C)c3ccccc3)cs2)CC1

Procedure:
tert-Butyl 4-{4-[(1Z)-4-phenylpent-1-en-1-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-4, 1.00 g) is dissolved in methanol and, at 40° C., hydrogenated under an H2-pressure of 10 bar in the presence of Pd/C (10%) for 5 hours. Filtration and removal of the solvent under reduced pressure gives tert-butyl 4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.00 g) as a colourless oil. This is deprotected analogously to Example II-2. This gives 850 mg of 4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidine hydrochloride. 169 mg are then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (100 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (180 mg) as a colourless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.ClC1C=C(N2[C:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26](Cl)[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=N2)C=CC=1F>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(Cl)cc2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 8A and 4-chlorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 43.4 g (87% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH3:10])[C:6]=2[C:11]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[OH:17][C:16]1[C:15]([OH:19])=[N:12][C:11]2[C:2](=[CH:3][CH:4]=[C:5]3[N:9]=[N:8][N:7]([CH3:10])[C:6]3=2)[N:1]=1
Reactant: Cn1nnc2ccc(N)c(N)c21
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cn1nnc2ccc3nc(O)c(O)nc3c21

Procedure:
A solution of 6.7-diamino-1-methyIbenzotriazole (1.63 g, 10 mmol) and oxalic acid dihydrate (2.0 g, 16 mmol) in 50 ml of 4M hydrochloric acid was refluxed on an oil bath for 2 h. The mixture was cooled on ice and the precipitate was collected by filtration, washed with water and ethanol affording 1.94 g (89%) of the title compound; m.p. >300° C.; IR (KBr): 3520-2400, 1700 cm-1; lH-NMR (DMSO-d6): 4.63 (s, 3H, CH3), 6.70 (d, J =9 Hz, lH; ArH), 7.60 (d, J =9 Hz, lH, ArH), 11.3 (very broad s, lH, OH), 12.1 (broad s, lH, OH).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>>[C:2]1([CH2:8][CH2:9]/[CH:10]=[CH:30]/[C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: COC(=O)c1ccc(/C=C/CCc2ccccc2)cc1

Procedure:
Using the conditions in example 1(A), (3-phenylpropyl)triphenylphosphonium bromide and methyl 4-formylbenzoate are condensed, providing methyl (E)-4-(4-phenyl-1-butenyl)benzoate as a colorless oil after chromatographic separation from the later-eluting (Z) isomer. This is reduced with lithium aluminum hydride in THF in the usual fashion to provide (E)-4-(4-phenyl-1-butenyl)phenylmethanol as a colorless oil. Oxidation with pyridinium dichromate in the usual fashion provides (E)-4-(4-phenyl-1-butenyl)benzaldehyde as a colorless oil after chromatography.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3].[C:43]([NH:53][CH2:54][C:55](O)=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[C:43]([NH:53][CH2:54][C:55]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3])=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:35])NC1SC(C2C=CC=C(C(=O)NC3CC3)C=2)=CN=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]([C:40]1[S:44][C:43]([NH2:45])=[N:42][C:41]=1[C:46]1[CH:51]=[CH:50][C:49]([C:52](=[O:57])[NH:53][CH:54]2[CH2:56][CH2:55]2)=[CH:48][CH:47]=1)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(OC(N1CCC[C@H]1C(O)=O)=O)C1C=CC=CC=1>>[CH3:36][O:37][C:38]([C:40]1[S:44][C:43]([NH:45][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[O:35])=[N:42][C:41]=1[C:46]1[CH:47]=[CH:48][C:49]([C:52](=[O:57])[NH:53][CH:54]2[CH2:56][CH2:55]2)=[CH:50][CH:51]=1)=[O:39]
Reactant: O=C(NC1CC1)c1cccc(-c2cnc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)s2)c1
Reactant: COC(=O)c1sc(N)nc1-c1ccc(C(=O)NC2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)nc1-c1ccc(C(=O)NC2CC2)cc1

Procedure:
In a similar procedure as described for the synthesis of Compound 5312 (Example 312), 2-amino-4-(4-cyclopropylcarbamoyl-phenyl)-thiazole-5-carboxylic acid methyl ester (0.098 g, 0.31 mmol) was treated with HATU (0.18 g, 0.46 mmol), DIEA (0.3 mL, 2.3 mmol), and (S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.12 g, 0.46 mmol) to furnish the desired product. 1HNMR (DMSO-d6) δ(ppm)12.90-12.88 (d, 1H), 8.89-8.85 (m, 1H), 8.51-8.50 (d, 1H), 7.86-7.72 (m, 4H), 7.37-7.33 (m, 2H), 7.15-7.09 (m, 2H), 5.09-4.87 (m, 2H), 4.51-4.49 (m, 1H), 3.74-3.72 (m, 3H), 3.53-3.47 (m, 1H), 2.88-2.84 (m, 1H), 2.45 (m, 1H), 1.91-1.87 (m, 3H), 0.71-0.59 (m, 4H); MS: 549.2 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:17][N:16]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2ccccc2)cn1
Temperature: 60 °C

Procedure:
Na2CO3 (1.117 mL, 2.234 mmol) followed by Pd(PPh3)4 (51.6 mg, 0.045 mmol) were added to a solution of iodobenzene (0.1 mL, 0.894 mmol) and 2-bromopyridine-5-boronic acid (271 mg, 1.340 mmol) in DMF (4 mL). The reaction was heated at 60° C. for 4 h, cooled and concentrated. The residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), and concentrated. Chromatography over silica eluting with 4:1 hexanes:EtOAc afforded the title compound as an off-white solid. LC-MS: calculated for C11H8BrN 234.09, observed m/e 236.5 (M+H)+ (Rt 1.72 min).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH:3]=[C:2]1[C:12]([OH:14])=[O:13].[H][H]>CO.O.[Pd]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCc2ccccc2O1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a suspension of commercially available chromone-2-carboxylic acid (50 g, 281 mmol) in methanol (500 mL), slurry of (10% Pd/C wet, 5 g) in water (10 mL) was added under nitrogen atmosphere. The mixture was hydrogenated at 60 psi at room temperature (RT) and further maintained hydrogen reservoir up to 60 psi for 2 h. The progress of reaction was monitored by TLC. Reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield chromane-2-carboxylic acid as off-white solid (44.7 g, 95%). m/z-178.02.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]#[N:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][C:21]#[N:22])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reaction time: 2 h

Procedure:
A mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (0.16 g, 0.50 mmol) and 10% palladium on carbon (20 mg) in methanol (5 mL) was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The reaction mixture was filtered and the filtrate concentrated to give the desired product (0.124 g, 86%), which was used directly in the next step. LCMS calculated for C15H19N4S (M+H)+: m/z=287.1. Found: 287.1.
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=O)C.N1C=CN=C1.CC1C(O)=CC=C2C=1OCC(C1C=CC(O)=CC=1)=C2>C(O)C>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[CH2:11][O:12][C:13]3[C:8]([CH:9]=2)=[CH:7][CH:6]=[C:5]([OH:4])[C:14]=3[CH3:15])=[CH:21][CH:20]=1
Reactant: COc1ccc(C2=Cc3ccc(OC(C)=O)c(C)c3OC2)cc1
Agent: Cc1c(O)ccc2c1OCC(c1ccc(O)cc1)=C2
Agent: c1c[nH]cn1
Solvent: CCO
Product: COc1ccc(C2=Cc3ccc(O)c(C)c3OC2)cc1

Procedure:
4′-Methoxy-8-methylisoflav-3-ene-7-ol was prepared from 7-acetoxy-4′-methoxy-8-methylisoflav-3-ene (0.11 g, 0.3 mmol) and imidazole (0.14 g) in ethanol (1.5 ml) as described for 8-methylisoflav-3-ene-4′,7-diol. Yield: (0.05 g, 53%) m.p. 103° C. 1H NMR (d6-acetone): δ 1.99 (s, 3H, CH3), 3.81 (s, 3H, OMe), 5.11 (s, 2H, H2), 6.43 (d, 1H, J 8.3 Hz, H6), 6.77 (bs, 1H, H4), 6.80 (d, 1H, J 8.3 Hz, H5), 6.95 (d, 2H, J 9.0 Hz, ArH), 7.44 (d, 2H, J 9.0 Hz, ArH). Mass spectrum: 282 (M, 9%); 267 (100); 268 (95); 134 (52).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C1(N=C=NC2CCCCC2)CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1.O>[CH3:16][O:15][C:13]([CH2:12][NH:11][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)=[O:14]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 50.0 g (0.400 mol) of nicotinic acid, 50.0 g (0.400 mol) of methyl glycinate hydrochloride, 90 g (0.440 mol) of dicyclohexylcarbodiimide, and 2 g of p-toluenesulfonic acid in 500 ml of dry pyridine was stirred overnight at room temperature. Filtration and evaporation in vacuo gave a heavy oil which was dissolved in 500 ml of water. After basification with ammonia the aqueous solution was extracted with 3×300 ml of dichloromethane. The organic phase was dried over magnesium sulphate, and removal of the solvent in vacuo gave crude 77 as a heavy yellow oil. Yield: 63.0 g (0.320 mol, 81%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]2[CH:19]=[C:20]([CH2:22][OH:23])[O:21][C:17]=2[CH:16]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]2[CH:19]=[C:20]([CH:22]=[O:23])[O:21][C:17]=2[CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CO)oc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C=O)oc2c1
Reaction time: 6 h
Yield: 68.5 %

Procedure:
A mixture of 6-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-methanol (21.0 g), activated manganese dioxide (52.0 g) and tetrahydrofuran (800 ml) was stirred at 60° to 65° C. for 6 hours. After the insoluble portion was filtered off, the filtrate was concentrated; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform (2:98, v/v), crystals of 6-(5-methyl-2-phenyl-4-oxazolylmethoxy) benzofuran-2-carbaldehyde (14.3 g, 69%) were obtained, which was then recrystallized from dichloromethane-isopropyl propyl ether to yield colorless prisms having a melting point of 137° to 138° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.P([O-])(OCC)(SCC)=[S:14]>O>[NH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1)=[S:14]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCOP([O-])(=S)SCC
Solvent: O
Product: COC(=O)c1ccc(C(N)=S)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of methyl-4-cyanobenzoate (5.0 g, 0.031 mol) and diethyl dithiophosphate (11.5 g, 0.062 mol) in water (100 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperatures and the solid was filtered and washed with water (100 mL). The solid was then dried in vacuo at 40° C. to give the crude product (4.74 g, 78%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CNC4)cc3N21
Yield: 65 %

Procedure:
A solution of 3-(4(R)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 1, SFC (Table 1, Method 1), Rt=3.374 min., 0.281 g, 0.61 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at ambient temperature for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #1-1, Enantiomer 1, SFC (Table 1, Method 1), Rt=4.541 min., 0.192 g, 65%) as yellow solid. LC/MS (Table 1, Method 5) Rt=2.074 min.; MS m/z: 364 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[C:17]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:41])[C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[CH:28]=[CH:29][CH:30]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl.ClCCN1C[CH2:50][O:49][CH2:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[C:17]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:41])[C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[CH:28]=[CH:29][CH:30]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:47][CH2:48][O:49][CH3:50]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(O)c(Cl)c3)n2)c1)c1c(F)cccc1F
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: COCCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl

Procedure:
The title compound was prepared from N-[3-(3-{2-[(3-chloro-4-hydroxyphenyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]-2,6-difluorobenzamide and 4-(2-chloroethyl)morpholine hydrochloride in a manner analogous to Example 126. 1H NMR (300 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.53 (s, 1H), 8.83 (d, 1H), 8.43 (d, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.93 (m, 1H), 7.80 (d, 1H), 7.58 (m, 1H), 7.54-7.44 (m, 3H), 7.33 (d, 1H), 7.24 (m, 2H), 7.11 (m, 1H), 7.05 (d, 1H), 6.52 (d, 1H), 4.10 (m, 2H), 3.55 (m, 4H), 2.69 (m, 2H), 2.48 (m, 4H); HRMS: calc. C36H31N7O3F2 (M+H)+ 682.2145 found 682.2153.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl.C(OC(C)C)(C)C>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:4])=[O:5]
Reactant: CN(CCCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCCCN)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
A solution of tert-butyl 5-(N-methyl-2-nitrophenylsulfonamido)pentylcarbamate 30d (31.5 g, 79 mmoles) and trifluoro acetic acid (29.2 mL, 5 eq) in DCM (300 mL) was stirred at RT until completion (˜16 h). The RM was then concentrated under vacuo, redissolved in DCM, washed with a saturated sodium bicarbonate aqueous solution (2 times), then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 23.7 g (quantitative yield) of N-(5-aminopentyl)-N-methyl-2-nitrobenzenesulfonamide 26a as a slightly yellow solid; m/z 302 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH2:28]([NH:35][C:9]1[C:10]([F:22])=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CN1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Solvent: c1ccncc1
Product: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Yield: 59.4 %

Procedure:
A mixture of 1-cyclopropyl-5,6,8-trifluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g), benzylamine (420 mg), and pyridine (5 ml) was heated at 100°-110° C. for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure. After addition of water to the residue, the mixture was acidified with 10% aqueous acetic acid and extracted with chloroform. The extract was dried and evaporated. The resulting crystals were recrystallized from ethanol-ether to give 5-benzylamino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (730 mg), m.p. 132°-133° C.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:10]1(Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.[H-].[Na+].[BH4-].[Na+]>CN(C=O)C.CO.O>[CH:10]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH2:1][OH:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: OCc1ccccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
Salicylaldehyde (1.0 g, 8.2 mmol) was dissolved in DMF (10 mL), cyclopentyl bromide (1.76 mL, 16.4 mmol) and sodium hydride (394 mg, 9.8 mmol) were added thereto, and then the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 90:10) to give an oily matter. The resulting oily matter was dissolved in methanol (10 mL), sodium borohydride (620 mg, 16.4 mmol) was added thereto, and then the mixture was stirred at room temperature for 2 hours. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (349 mg, yield 25%).