Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([C:38]#[CH:39])=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([C:39]#[C:38][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:40])=[CH:33][CH:34]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 62.9 %

Procedure:
Under the conditions of example 5 A, 1 g of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is reacted with 384 mg of 4-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-7% ethyl acetate. 670 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethinyl]-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:2]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[OH:35])[N:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:35])[C:28]=1[C:19]1[N:18]=[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:2]2)[C:26]2[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Reactant: COCCOC(=O)NC[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Yield: 88.1 %

Procedure:
To a solution of 2-methoxyethyl ((R)-piperidin-3-yl)methylcarbamate (0.24 g, 1.1 mmol) and 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (250 mg, 0.865 mmol) in CH2Cl2 was added triethylamine (2.41 mL, 1.73 mmol). After stirring the reaction at room temperature for 2 h, it was quenched with water and then extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0%-10% EtOAc in CH2Cl2 yielded 2-methoxyethyl ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (357 mg, 88%). LC/MS: m/z 469.5 (M+H)+ at 2.30 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: N
Product: c1cncc(-c2noc(-c3ccc4c(c3)OCO4)n2)c1

Procedure:
The title compound was prepared according to method C using benzo[d][1,3]dioxole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.22 (s, 2H), 7.20 (d, J=8.1 Hz, 1H), 7.61-7.69 (m, 2H), 7.81 (dd, J=8.1, 1.7 Hz, 1H), 8.42 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.81 (dd, J=4.7, 1.7 Hz, 1H), 9.24 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 268 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33](=[N:35][OH:36])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:48](OCC)(=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:33]1[CH2:34][C:48]([OH:54])([C:49]([O:51][CH2:52][CH3:53])=[O:50])[O:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=NO)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(O)CC(c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)=NO1
Reaction time: 1 h
Yield: 21 %

Procedure:
To a stirred solution of 1-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-N-hydroxyethanimine (10 g, 44 mmol) was added drop wise 2 M n-ButLi in hexane (45 mL, 44 mmol) at −78° C. and the stirring was continued for 1 hour at −78° C. then for ½ hour at room temperature. After recooling at −78° C., a solution of diethyl oxalate (3.22 g, 22 mmol) in THF (50 mL) was cannuled into the cloudy solution. The mixture was warmed at rt over 16 hours before the addition of a NH4Cl saturated solution (100 mL). The organic and aqueous layers were separated and the latter was diluted with ethyl acetate and thoroughly washed with brine. After drying over Na2SO4, the solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane 7/5, to provide the title compound (2.7 g, yield 17%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([OH:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20]([CH2:22]P(OC)(OC)=O)=[O:21]>O>[CH3:18][O:19][C:20](=[O:21])/[CH:22]=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[C:1]([OH:3])=[O:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)/C=C/c1cccc(C(=O)O)c1
Temperature: 2.5 °C
Reaction time: 17 h

Procedure:
3-Carboxybenzaldehyde (25 g, 0.167 mol) and K2CO3 (69 g, 0.499 mol) were added to water (250 mL) and cooled to 0-5° C. Trimethyl phosphonoacetate (32.3 mL, 0.2 mol) was charged dropwise maintaining the reaction temperature below 15° C. The reaction was warmed and stirred at RT for 17 h. The mixture was acidified to pH˜1, filtered and dried in vacuo to afford the product as an off-white solid (37.25 g, >100%—slightly wet). 1H NMR (300 MHz, CD3OD) δ: 8.23 (1H, s), 8.06 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=7.5 Hz), 7.75 (1H, d, J=15.9 Hz), 6.61 (1H, d, J=16.2 Hz), 7.54 (1H, t), 3.81 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][CH2:16][C:17](Br)=[O:18].BrCC(NC1C=COC=1C(=O)C1C=CC=CC=1)=O>>[Br:15][CH2:16][C:17]([NH:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:18]
Reactant: Nc1occc1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C(CBr)Nc1ccoc1C(=O)c1ccccc1
Product: O=C(CBr)Nc1occc1C(=O)c1ccccc1

Procedure:
2-Amino-3-benzoylfuran may be acylated with bromoacetyl bromide using the procedure for compound 7. When compound 6 is replaced in this procedure with compound 29 the title structure is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:21][CH:20]=1)=[O:17]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:16]([N:11]3[CH2:12][CH2:13][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=4)[CH2:9][CH2:10]3)=[O:17])=[CH:20][CH:21]=2)=[N:27][CH:28]=1
Reactant: Nc1cccc(C2CCNCC2)c1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1cccc(C2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)c1

Procedure:
The title product was prepared from 4-(3-aminophenyl)piperidine (released form the correspondent hydrochloride by a standard procedure) and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (reaction performed in a mixture of dichloromethane and dimethylformamide, 5:3). 1.7 M HCl in ethyl acetate was added to the pooled fractions containing the title product, and the fractions was evaporated to dryness (7%, light yellow solid). HPLC-MS m/z=(M+1) 458.0, Rt: 3.09 min.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:35](=O)[NH:36][CH2:37][CH2:38][NH:39]C)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[N:36]([CH2:37][CH2:38][NH2:39])[CH3:35])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CNCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N(C)CCN)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
A solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.25 mmol) in DMF is added (2-methylamino ethyl)-carbamic acid tert-butyl ester (53 mg, 0.25 mmol), HBTU (140 mg, 0.38 mmol), and DIPEA (0.088 mL, 0.51 mmol). After 48 h stirring at room temperature, the resulting mixture is concentrated and diluted with saturated NaHCO3 solution and extracted with ethyl acetate (3×100 mL). The combine organics are dried over Na2CO3 and concentrated to give a reddish residue. Followed by deprotection using General Procedure A to give 2-{5-[(2-amino-ethyl)-methyl-carbamoyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 77%). MS(ESI) m/z 451.3 (M+H)+
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([O:17]C)=[O:16])=[CH:3][CH:2]=1.[OH-].[Na+].CC(O)=O>C1C2C(=O)C3C(=CC=CC=3)NC=2C=CC=1>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([C:15]([OH:17])=[O:16])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2cc3ccccc3nc12
Agent: O=c1c2ccccc2[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2cc3ccccc3nc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To methyl acridine-4-carboxylate, prepared in Example 4,(183 mg), was added a degassed solution of NaOH in aqueous EtOH (1:1,2M)(35 ml). The mixture was stirred for 3 hours at 50° C., when a clear solution was obtained, then neutralised with glacial AcOH. Extraction with EtOAc (3×15 50 ml) followed by chromatography on silica gel, eluting with EtOAc/petroleum ether (1:4), gave acridine-4-carboxylic acid (160 mg, 87%), mp (Me2CO) 196-197° C. (lit, mp 202-204° C.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:10]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:9]=3[O:8][C:7]=2[CH:25]=1.C(Cl)Cl.B(Br)(Br)[Br:30]>CO>[BrH:30].[BrH:30].[CH3:24][C:21]1[CH:22]=[CH:23][C:9]2[O:8][C:7]3[CH:25]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=3[CH2:12][CH:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:10]=2[CH:20]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1)Oc1ccc(C)cc1C(N1CCN(C)CC1)C2
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Cc1ccc2c(c1)C(N1CCN(C)CC1)Cc1ccc(O)cc1O2

Procedure:
4.0 G. of 4-[10,11-dihydro-3-methoxy-8-methyl-dibenz[b,f]oxepin-10-yl]-1-methyl-piperazine are dissolved in 600 ml. of methylene chloride, treated with a solution of 8.9 g. of boron tribromide in 90 ml. of methylene chloride and stirred at room temperature for 20 hours. The residue is taken up in 150 ml. of methanol, boiled at reflux for 30 minutes with active carbon, filtered, concentrated to about 70 ml., treated with ether until turbidity sets in, and there is obtained crystalline 10,11-dihydro-8-methyl-10-(4-methyl-1-piperazinyl)-dibenz[b,f]-oxepin-3-ol dihydrobromide having a melting point of 176° C. (with decomposition).
Reaction SMILES: CN1CCOCC1.[F:8][C:9]([F:29])([F:28])[C:10]1[N:18]2[C:13]([C:14]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=32)=[CH:12][CH:11]=1.[C:30]([S:34]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)=[O:35])([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:30]([S:34]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([N:25]2[CH2:24][CH2:23][C:14]3([C:13]4=[CH:12][CH:11]=[C:10]([C:9]([F:8])([F:28])[F:29])[N:18]4[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15]3)[CH2:27][CH2:26]2)=[O:41])=[CH:43][CH:44]=1)=[O:35])([CH3:33])([CH3:31])[CH3:32]
Reactant: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Reactant: CC(C)(C)S(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)S(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C(F)(F)F)ccc23)cc1
Temperature: 50 °C
Yield: 45.2 %

Procedure:
4-methyl morpholine (1.96 mL, 17.8 mmol) was added to a mixture of 1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (1.45 g, 3.56 mmol), 4-tert-butylsulfinylbenzoic acid (807 mg, 3.56 mmol), EDCI (1.03 g, 5.35 mmol), 1-hydroxybenzotriazole (723 mg, 5.35 mmol) and DMF (14.5 mL) at room temperature. The mixture was heated at 50° C. overnight before it was cooled to room temperature and partitioned between ethyl acetate and 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (0-30% ethyl acetate/CH2Cl2, then 0-100% ethyl acetate/hexanes) to provide (4-tert-butylsulfinylphenyl)-[1′-(trifluoromethyl)spiro-[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (831 mg, 44%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.68-7.62 (m, 4H), 7.57 (d, J=8.1 Hz, 1H), 7.33-7.26 (m, 2H), 7.24-7.17 (m, 1H), 7.02 (d, J=4.0 Hz, 1H), 6.41 (d, J=4.0 Hz, 1H), 4.52-4.37 (m, 1H), 3.49 (s, 2H), 3.26-3.13 (m, 1H), 2.16-1.96 (m, 3H), 1.96-1.80 (m, 1H), 1.09 (s, 9H). ESI-MS m/z calc. 516.2, found 517.2 (M+1)+; Retention time: 1.94 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](Cl)=[O:32])[CH:26]=1>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:27]5[CH:28]=[CH:29][CH:30]=[N:25][CH:26]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccnc1
Yield: 43 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol), N-methylpyrrolidone (3 mL) and pyridine-3-carbonylchloride hydrochloride (107 mg, 0.60 mmol), and in the same manner as in Example 162, the title compound (89 mg, yield 43%) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]>C1COCC1.CO.O.[Li+].[OH-]>[C:27]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]3[CH2:21][CH2:22][C@@H:23]([F:26])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)[C@H]2CC[C@@H](F)CC2)CC1

Procedure:
5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10 mg, 0.021) was dissolved in a mixture of THF, MeOH and H2O (3:2:1) (2 mL) and 1N LiOH (0.1 mL) was added. Rest of the procedure has been described earlier (example 3, step VIII). Pure 5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid was obtained after chromatography over silica gel (5% MeOH in DCM as eluent) (5 mg, 51%).
Reaction SMILES: [OH2:1].O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:17][CH2:16]3)[C:11]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:6][CH:5]=1.[OH-].[Na+:35]>CO>[OH2:25].[OH2:1].[Na+:35].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH2:22][CH2:23][C:24]([O-:26])=[O:25])[CH2:17][CH2:16]3)[C:11]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCC(=O)N1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])CCC(=O)N1CCN(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 194.4 %

Procedure:
A slurry of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H- pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, dihydrate (150 mg, 0.31 mmol) from above in methanol (10 mL) was treated with a solution of sodium hydroxide (12 mg, 0.31 mmol) in methanol (2 mL). The reaction was stirred at room temperature for 15 minutes until dissolution was completed. The solvent was removed in vacuo. The residue was treated with tetrahydrofuran and filtered and air dried to give 150 mg (97%) of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1-H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid monosodium salt dihydrate as a solid. Anal. Calc'd. for C22H21ClN5O3Na.2H2O: C, 53.07; H, 5.06; N, 14.07. Found: C, 52.81; H, 5.11; N, 13.90.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:21]1[O:28][C@H:27]([CH2:29]O)[C@@H:25]([OH:26])[C@H:23]([OH:24])[CH2:22]1.C(Br)(Br)(Br)[Br:39].CO>N1C=CC=CC=1>[Br:39][CH2:29][C@H:27]1[O:28][C@@H:21]([O:20][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22][C@@H:23]([OH:24])[C@@H:25]1[OH:26]
Reactant: BrC(Br)(Br)Br
Reactant: OC[C@H]1O[C@@H](OCc2ccccc2)C[C@@H](O)[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CO
Product: O[C@H]1[C@H](O)C[C@H](OCc2ccccc2)O[C@@H]1CBr
Temperature: 50 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (4.5 g, 17.3 mmol, 2.2 eq) in pyridine (30 mL) was added dropwise to a cooled solution of Compound 1 (2.0 g, 7.9 mmol) and CBr4 (3.1 g, 9.4 mmol) in pyridine (30 mL) at zero degrees C. The mixture was then heated at 50° C. for 10 hours. After cooling, methanol (5 mL) was added dropwise, and the mixture was concentrated. The product was purified by flash column chromatography with CHCl3—MeOH (32:1) to give 1.82 g (yield 73 percent) of Compound 2.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>CO>[CH2:14]([NH:17][C:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1)=[O:12])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: COC(=O)c1nc(SC)ncc1Br
Solvent: CO
Product: C=CCNC(=O)c1nc(SC)ncc1Br
Temperature: 90 °C
Yield: 89.6 %

Procedure:
A solution of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (Preparation 30, 1.00 g, 3.80 mmol) was dissolved in methanol (16 mL), treated with allylamine (3.00 mL, 40.0 mmol) and heated to 90° C. for 18 hours. The mixture was concentrated in vacuo and the residue purified by silica gel column chromatography eluting with 0 to 5% EtOAc in cyclohexanes to give the title compound (981 mg, 90%).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1
Reactant: Clc1nccs1
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc(Oc2nccs2)cc1
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
A mixture of 2-chlorothiazole (5.0 g), ethyl 2-(4-hydroxyphenyl)propionate (8.1 g), potassium carbonate powder (8.65 g) and dimethylformamide (80 ml) is stirred at 150°-155° C. for 2.5 hours. The solvent is distilled out under reduced pressure. To the residue is added water and extracted with ether. The extract is washed with a 10% aqueous solution of sodium hydroxide and water and dried. The ether is evaporated. The residue is subjected to chromatography using silica gel and eluted with 50% benzene-hexane, benzene and 10% ether-benzene to yield ethyl 2-[4-(2-thiazolyloxy)-phenyl]propionate (5.8 g). IR νmaxCCl4 1740, 1240, 700 cm-1.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]([O:20]C)=O)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.CO.C(O)(=O)C.[NH3:28]>O>[C:18]([CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:20])[NH2:28]
Reactant: N
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: NC(=O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
2.1 g. of the product from Example 81 is dissolved in a mixture of water (40 ml.) and concentrated ammonia (40 ml.). After one hour the reaction mixture is concentrated to 1/3 volume, and applied to a column of Dowex 50 resin in the hydrogen cycle. The product is eluted with water. The aqueous is extracted with ethyl acetate and then concentrated to dryness to yield 1.4 g. of the named product Rf : 0.50 (silica gel-Chloroform:methanol:acetic acid:water).
Reaction SMILES: [O:1]=[O+][O-].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=CC)[C:13]=1[OH:21]>C(OCC)(=O)C.C(O)(=O)C>[OH:21][C:13]1[C:12]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Cl:4])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:18]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC=Cc1cccc(Sc2ccccc2Cl)c1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=Cc1cccc(Sc2ccccc2Cl)c1O

Procedure:
Ozone gas was introduced into a solution of 2-(2-chlorophenylthio)-6-(1-propenyl)phenol (26 g) in a mixture of ethyl acetate (200 ml) and acetic acid (10 ml) at temperature below 0° C. with stirring for an hour. The precipitates were collected by filtration, washed with ethyl acetate and then dried to give 2-hydroxy-3-(2-chlorophenylthio)benzaldehyde (15.9 g), mp. 111°-112.5° C. The filtrate and washings were combined, washed with dil. aqueous sodium hydrogen sulfite, saturated aqueous sodium bicarbonate and water in turn, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was washed with methanol and dried to give the same product (3.2 g). Total yield 19.1 g.