Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH2:21][CH2:20][C@H:19]2[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:18]2[CH2:17][CH2:16][C@@:13]2([CH2:14][CH3:15])[C@H:9]3[C@@H:10](OC(=O)C(C)(C)C)[CH2:11][C:12]2=[O:22])[CH:4]=1.[C-:30]#[C-:31].[Li+].[Li+]>>[C:30]([C@:12]1([OH:22])[CH:11]=[CH:10][C@H:9]2[C@H:8]3[C@H:18]([CH2:17][CH2:16][C@:13]12[CH2:14][CH3:15])[C@@H:19]1[C:5](=[CH:4][C:3](=[O:2])[CH2:21][CH2:20]1)[CH2:6][CH2:7]3)#[CH:31]
Reactant: [C-]#[C-]
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)C(C)(C)C)CC2=O
Agent: [Li+]
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Analogously to Example 1(b), 2.8 g of 3-methoxy-18-methyl-15α-trimethylacetoxy-3,5-estradien-17-one is reacted with lithium acetylide and worked up. Recrystallization from acetone/hexane yields 1.6 g of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one, melting point 197° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid, m.p. 114° C. and MS: m/e=373 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH2:11](OC=C(C#N)C#N)C>C(O)(C)C>[N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1][CH:11]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCOC=C(C#N)C#N
Solvent: CC(C)O
Product: N#Cc1ccc2nc[nH]c2c1

Procedure:
A mixture of 3,4-diaminobenzonitrile (2) (1.0 g) and (ethoxymethylene)malononitrile (1.4 g) was refluxed in 50 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo to provide the title compound, 3H-benzo[d]imidazole-5-carbonitrile (3).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4OS(C(F)(F)F)(=O)=O)[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[K+].[Br-]>O1CCOCC1.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>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:19]2[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=2[C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:13]=2)=[CH:39][CH:38]=1
Reactant: O=S(=O)(Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: C1COCCO1
Product: Fc1ccc(-c2cc(C(F)(F)F)ccc2-c2cc(Oc3ccc4cccnc4c3)ncn2)cc1
Temperature: 140 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethylphenyl ester, (Example 192(a)), (100 mg, 0.19 mmol), 4-fluorophenyl boronic acid (41 mg, 0.29 mmol, Aldrich), K3PO4 (82 mg, 0.39 mmol), KBr (35 mg, 0.29 mmol) and Pd(PPh3)4 (11 mg, 0.010 mmol, Strem) in dioxane (2.0 mL) was stirred and heated by microwave synthesizer at 140° C. for 10 min. The mixture was partitioned between CH2Cl2 and 1 N NaOH. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (gradient 0.5 to 3.0% MeOH/CH2Cl2) afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 462 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(NCC)C.[OH-].[Na+]>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.O1CCCC1>[C:22]1([C:28]#[C:29][C:2]2[CH:3]=[C:4]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)[CH:5]=[N:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)c2)CC1
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(C#Cc3ccccc3)c2)CC1

Procedure:
A mixture of 1-(5-bromo-3-pyridyl)-4-tert-butoxycarbonylhomopiperazine (3.5 g, 9.8 mmol), phenylacetylene (2.0 g, 19.6 mmol), tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol), diethylamine (1.4 g, 19.6 mmol) and tetrahydrofuran (50 ml) was refluxed for 5 hours. Aqueous sodium hydroxide (75 ml, 1M) was added. The mixture was extracted twice with ethyl acetate. The mixture was purified by chromatography on silica gel using ethyl acetate:petroleum (1:1) as solvent. Yield 0.54 g, 7.3%.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=3[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])C(O)=O>>[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])[C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:17]
Reactant: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Reactant: O=C(O)c1ccc(O)c(O)c1
Product: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2ccc(O)c(O)c2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-2,5-dimethoxyaniline (531 mg, 0.7 mmol, example 82, step A) as described for example 82 (step B) using 3,4-dihydroxybenzoic acid (164 mg, 1.1 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using first 10% then 30% EtOAc/CH2Cl2 containing 1% AcOH. The title compound was obtained as yellow crystals (164 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:30]1([CH2:36][CH2:37][NH:38][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[NH:10]2)=[O:29])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: NCCN1CCOCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCCN2CCOCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol), 2-morpholin-4-yl-ethylamine (36.0 mg, 0.28 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by SiO2 flash column (20-100% of EtOAc in Hexanes) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (60.5 mg, 86.4%) as a white amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[CH:11][C:10]=1[O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[BH4-].[Na+].O>C(#N)C.C(Cl)Cl.CO>[CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)NCCCc2ccc(OCc3ccccc3)c(OC)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(CC2NCCCc3cc(OC)c(OCc4ccccc4)cc32)cc1OC
Temperature: 0 °C

Procedure:
A mixture of N-[3-(4-benzyloxy-3-methoxy-phenyl)-propyl]-2-(3,4-dimethoxy-phenyl)-acetamide (6.04 g, 13.43 mmol) and POCl3 (4.1 ml, 44.78 mmol) in anhydrous acetonitrile (350 ml) was stirred at reflux for 5 h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (120 ml). The solution was cooled to 0° C. and NaBH4 (3.50 g, 92.70 mmol) was added portionwise. After stirring at 0° C. for 2 h under nitrogen, the reaction mixture was poured into H2O and extracted three times with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the title compound as a racemic mixture (2.44 g, 5.62 mmol, 42%, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([C:42]12[CH2:49][CH2:48][C:45]([CH:50]=[O:51])([CH2:46][CH2:47]1)[CH2:44][CH2:43]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:27]([N:34]([C:42]12[CH2:47][CH2:46][C:45]([CH:50]([C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]4[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:4]=34)[OH:51])([CH2:44][CH2:43]1)[CH2:48][CH2:49]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C12CCC(C=O)(CC1)CC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C34CCC(N(Cc5ccccc5)C(=O)OC(C)(C)C)(CC3)CC4)c(Cl)cnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
To a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.33 g, 3.06 mmol, Adesis) in THF (25 mL) at about −78° C. was added n-BuLi (1.6 M solution in hexanes, 2.00 mL, 3.20 mmol) at such a rate that the internal temperature did not exceed about −70° C. The reaction mixture was stirred for about 45 min and a solution of tert-butyl benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.05 g, 3.06 mmol) in THF (6 mL) was added dropwise. The reaction mixture was stirred at about −78° C. for about 1 h and was slowly warmed to ambient temperature and stirred for about 1 h. Saturated aqueous NH4Cl and EtOAc (10 mL each) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The remaining oil was purified by silica gel chromatography eluting with a gradient of 0-40% EtOAc in heptane to give tert-butyl benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.27 g, 64%) as a clear colorless oil: LC/MS (Table 1, Method o) Rt=3.78 min; MS m/z: 652 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:20][CH:19]=[CH:18][C:8]=2[N:9]=[C:10]([CH2:12][C:13](OCC)=[O:14])[N:11]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:20][CH:19]=[CH:18][C:8]=2[N:9]=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=1
Reactant: CCOC(=O)Cc1nc(-c2ccco2)c2sccc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCCc1nc(-c2ccco2)c2sccc2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.4 %

Procedure:
A solution of ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-acetate (0.10 g, 0.35 mmol) in dichloromethane (13 mL) at −75° C. was treated dropwise with di-iso-butylaluminium hydride (0.87 mL, 1.0-M), stirred for 17 h, warmed to ambient temperature and partitioned between Rochelle's salt and dichloromethane. The combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc) to give the title compound (21 mg, 25%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)NCCc1ccncc1
Reaction time: 8 h
Yield: 23.7 %

Procedure:
Methanesulphonyl chloride (3.5 g.) was added slowly to 4-(2-aminoethyl)pyridine (3.6 g.) and triethylamine (3.0 g.) in chloroform (40 ml.). The temperature was maintained below 40° C. during the addition, after which the orange solution was left to stand at room temperature overnight. Water (50 ml.) was then added, the chloroform phase was separated, and the aqueous phase extracted with chloroform (100 ml.). The two chloroform solutions were combined, dried (MgSO4) and taken to dryness in vacuo to give a yellow oil which solidified immediately. This solid was crystallized from ethanol to yield white crystals of 4-(2-methanesulphonamidoethyl)pyridine (1.4 g.).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[NH:20][S:19]2(=[O:25])=[O:24])=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=1.[OH-].[K+].Cl>O.CO.CC#N>[CH2:27]([O:26][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N:18]1[CH2:22][C:21](=[O:23])[NH:20][S:19]1(=[O:25])=[O:24])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:34])=[O:2])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 60 °C

Procedure:
To a solution of {2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-phenyl}-acetic acid methyl ester (Example 512, step C) in water/MeOH/MeCN (1:1:1) is added KOH and the mixture is heated at 60° C. for 1 h. The mixture is cooled to RT, acidified with 1N HCl and extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[O:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:21])=[CH:23][CH:24]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 99.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{[5-(4-chlorophenyl)-2-methyl-3-furyl](cyclohexyl)methoxy}benzoic acid (120 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (143 mg, 93%) as an amorphous compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(O)CCCCl
Reactant: CC(=O)OC(C)=O
Product: CCCCCC(CCCCl)OC(C)=O

Procedure:
A mixture of 1-chloro-4-nonanol (111.99 g.; 0.627 mole) and acetic anhydride (128.0 g.; 1.254 moles) is heated on a steam bath for 11/2 hours.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:8]1[C:3]([C:1]#[C:2][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH:39]4[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]4)=[CH:35][CH:34]=3)[N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Reactant: C#Cc1ncccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylpyridin-3-yl)acetate (I120) (0.100 g, 0.571 mmol) in THF (1 mL) and triethylamine (0.199 mL, 1.43 mmol) was added to a mixture of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I24) (0.217 g, 0.476 mmol), Pd(PPh3)2Cl2 (0.033 g, 0.048 mmol), Cu(I)I (0.014 g, 0.071 mmol) and triphenylphosphine (0.019 g, 0.071 mmol) in dimethylformamide (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes then cooled, degassed for 10 minutes and heated under microwave irradiation at 120° C. for a further 20 minutes. The cooled mixture was diluted with ethyl acetate and the resulting solution passed through a plug of Celite, washing with ethyl acetate (250 mL). The volatiles were removed to give a brown solid which was chromatographed (Biotage Isolera: 25 g silica cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I147) (0.061 g, 22%); 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.72 (dd, J=7.9, 1.3 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.54 (s, 1H), 7.35 (dd, J=7.9, 4.7 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 4.30-4.06 (m) 3.95 (s, 2H), 3.71 (s, 3H), 2.84-2.58 (m, 3H), 2.06-1.98 (m), 1.70-1.66 (m, 2H), 1.69-1.51 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][OH:39])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (54 mg) and 2-bromoethanol (0.03 ml) were added to the suspension, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (34 mg, yield 61%).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:20]([NH:27][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([NH:10][C:4]2[C:5]3[NH:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.9 %

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), benzylamine (96 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→50:50). Ethyl acetate and diethyl ether were added and the precipitate was collected by filtration to give the title compound (128 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:19])=O)=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1>S(Cl)(Cl)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:19])=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C(=O)OC2c1ccc(F)cc1

Procedure:
A suspension of 1-(4-fluoro-phenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carboxylic acid amide (13.6 g, 0.05 mole) in thionyl chloride (40 mL) and DMF (0.25 mL) was heated at reflux for 2 hours. The thionyl chloride was then evaporated, and the residue was dissolved in hot IPA (100 mL). On cooling, crystals of the title compound were formed. Yield: 7.8 g (62%). 1H NMR (d6-DMSO): δ 6.87 (s, 1H), 7.26 (t, 2H), 7.42 (dd, 2H), 7.58 (d, 1H), 8.18 (dd, 1H), 8.48 (s, 1H).