Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[F:33][C:34]1[CH:66]=[C:65]([C:67]([F:70])([F:68])[F:69])[CH:64]=[CH:63][C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)cc3)cc2C1=O
Yield: 94 %

Procedure:
The compound of example 192 was prepared analogous to compound of example 98 by hydrolysis of compound of example 191.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(O)[C:17]2[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].S(Cl)([Cl:22])=O>>[CH3:1][O:2][C:3]([C:5]1([Cl:22])[C:17]2[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4]
Reactant: COC(=O)C1(O)c2ccccc2-c2ccc(F)cc21
Reactant: O=S(Cl)Cl
Product: COC(=O)C1(Cl)c2ccccc2-c2ccc(F)cc21

Procedure:
A mixture of 2-fluoro-9-hydroxy-9H-fluorene-9-carboxylic acid methyl ester (5) (4.00 g, 15.5 mmol) and 50 mL thionyl chloride was refluxed 3 h. After the thionyl chloride was removed on the rotavapor, the material was redissolved in 50 mL benzene and the benzene then evaporated to remove trace thionyl chloride. The crude product, 4.3 g (100%), was used without further purification.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH:32]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][C:36]=1[F:42].CC(O)=O>CCOC(C)=O.ClCCCl>[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][CH2:32][C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[N:26][CH:27]=2)=[CH:37][C:36]=1[F:42]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: COC(=O)c1ccc(-c2cc(F)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(F)ccc2CNc2ccc(Br)c(F)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (491 mg, 2.3 mmol) was added to a DCE solution (4 mL) of methyl 5-(5-fluoro-2-formylphenyl)picolinate (300 mg, 1.2 mmol), 4-bromo-3-fluoroaniline (242 mg, 1.3 mmol), and AcOH (0.27 mL, 4.6 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].CP(=O)(C)CCCCCCCCCCCC.C(Cl)([Cl:34])=O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:34])=[O:7]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CCCCCCCCCCCCP(C)(C)=O
Solvent: Cc1ccccc1C
Product: COc1cc(C(=O)Cl)cc(OC)c1OC

Procedure:
A mixture of 100 g of 3,4,5-trimethoxybenzoic acid, 150 g of xylene and 0.1 g of dimethyl-dodecyl-phosphine oxide is treated with phosgene at 100°C in the apparatus described for example 1. After a lapse of abt. 1 hour and phosgene consumption of 140 g the absorption of phosgene is terminated. At the end of a two-hours-postreaction a yellow solution of 3,4,5-trimethoxy-benzoylchloride is obtained. The yield in dissolved acid chloride is approx. 106 g, corresponding to 97.5% of the theoretical yield, calculated on the acid used. The solution may be used directly for further reactions after having eliminated the remaining phosgene by means of nitrogen or by distillation of a part of the solvent. But it is also possible to isolate the trimethoxy-benzoylchloride in its pure form by means of vacuum distillation (boiling point: 137°C/1.5 torr. softening point: 80 to 81°C).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:10]([O:13][CH3:14])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:17])=O>C1C=CC=CC=1>[CH2:1]1[O:12][C:11]2[C:10]([O:13][CH3:14])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc2c1OCO2
Solvent: c1ccccc1
Product: COc1cc(C(=O)Cl)cc2c1OCO2

Procedure:
3,4-Methylenedioxy-5-methoxybenzoic acid (39.23 g, 0.2 mol) was dissolved in dry benzene, thionyl chloride 47.6 g (28.8 ml, 0.4 mol) was added under stirring, the resulting solution was refluxed for 15 hr, then the solvent and excessive thionyl chloride were removed by distillation under reduced pressure to give pure 3,4-methylenedioxy-5-methoxy-benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Br)cn1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)Nc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Br)cn1
Temperature: 210 °C
Yield: 87.2 %

Procedure:
Two capped microwave reaction vials each containing a solution of N-(5-bromo-4-chloropyridin-2-yl)pivalamide (0.55 g, 1.89 mmol), benzyl 4-(aminomethyl)piperidine-1-carboxylate (1.07 g, 2 eq.) and triethylamine (0.80 mL, 3 eq.) in NMP (3.8 mL) were heated at 210° C. by microwave irradiation for 1.5 hr and then allowed to cool. The contents of the two vials were combined and partitioned between EtOAc (15 mL) and sat. NaHCO3 (150 mL). The organic layer was retained whilst the aqueous was further extracted with EtOAc (15 mL). The organic extracts were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The crude material was purified by chromatography on a 40+M Biotage silica column, eluting with a gradient of EtOAc in dichloromethane, to give the title compound as a clear oil (0.83 g, 43%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[CH2:50]([NH:52][CH2:53][CH3:54])[CH3:51]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:26])[F:25])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:44])[CH3:45])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:52]([CH2:53][CH3:54])[CH2:50][CH3:51])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: CCNCC
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: CCN(CC)CCc1ccc(OC)c(C2(N3C[C@H](O)C[C@H]3C(=O)N(C)C)C(=O)N(S(=O)(=O)c3ccc(OC)cc3OC(F)(F)F)c3ccc(Cl)cc32)c1

Procedure:
With 500 mg of the compound obtained in Example 219 and diethyl amine (0.16 ml) as starting materials, 180 mg of the title compound (light yellow amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: Cl.Cl[C:3]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:4].[C@H:13]1([NH:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:33])[CH:29]=3)[N:24]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>C(N(CC)CC)C>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:3](=[O:4])[NH:33][C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:22][C@H:13]2[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]2)[CH:32]=[CH:31]3)[CH2:7][CH2:8]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN1CCC(OC(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 11 described in example 138 from triethylamine, 4-chlorocarbonyloxy-1-methylpiperidine hydrochloride (CAS no: 127595-09-9) and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=215.3 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.Br[C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]2[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]2[CH:24]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1ccc2nc(Br)cn2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cc4ccccc4o3)cn2c1
Temperature: 25 °C
Yield: 0.7 %

Procedure:
Benzofuran boronic acid (0.289 mmol), 2-bromo-6-methoxyimidazo[1,2-a]pyridine (0.263 mmol), Pd(dppf)Cl2 (0.013 mmol) and K2CO3 (aq.) were stirred in DMF at 80° C. under argon for 1 h. The reaction mixture was allowed to cool to r.t. and brine was added. The reaction mixture was extracted with CH2Cl2 and the organic phase was filtered. The solvents were removed under reduced pressure and the residue purified by reverse phase HPLC to afford the title compound (0.5 mg). 1H NMR δ ppm 7.95 (s, 1 H) 7.67 (d, 1 H) 7.65-7.60 (m, 1 H) 7.58-7.51 (m, 2 H) 7.33-7.20 (m, 3 H) 7.03 (dd, 1 H) 3.86 (s, 3 H); MS m/z 265 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][N:18]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C(=O)O)cn2)CC1
Yield: 61.8 %

Procedure:
A solution of 14-2 (650 mg, 1.2 mmol), 1N LiOH (3 mL), and THF (5 mL) was stirred at ambient temperature for 20 h. The reaction mixture was then washed with EtOAc followed by acidification with 5% KHSO4, then extraction with EtOAc. The EtOAc extract was washed with brine, dried (MgSO4) and concentrated to give 14-3 (260 mg) as a white solid. Rf 0.64 (silica, 10:2:2 (CH2Cl2 /CH3OH/AcOH).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].Cl.[CH3:23][NH:24][O:25][CH3:26].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:26][O:25][N:24]([CH3:23])[C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (420 mg), N,O-dimethylhydroxylamine hydrochloride (150 mg), triethylamine (0.24 mL), 1H-1,2,3-benzotriazol-1-ol (300 mg) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (380 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-1:1), and the obtained crystals were recrystallized from ethyl acetate-diethyl ether to give the title compound (395 mg, yield 83%) as pale-yellow needle crystals. melting point 180-181° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:21]=[C:20]([Si](C)(C)C)[C:11]2[C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:13]=3[NH:14][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:27]I>C(O)C.F[B-](F)(F)F.[Ag+]>[CH2:1]([N:8]1[CH:21]=[C:20]([I:27])[C:11]2[C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:13]=3[NH:14][C:10]=2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc2[nH]c3c(=O)n(Cc4ccccc4)cc([Si](C)(C)C)c3c2c1
Reactant: II
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Cc1cnc2[nH]c3c(=O)n(Cc4ccccc4)cc(I)c3c2c1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
Compound 28 (2.5 g, 6.93 mmol) dissolved in dry ethanol (200 mL) and stirred under nitrogen at 0° C. Silver tetrafluoroborate (1.45 g, 7.45 mmol) was added, and the solution stirred for 10 minutes. Iodine (1.85 g, 7.3 mmol) was added, and the reaction stirred 1 h as a precipitate began to form. After evaporation of the solvent, the solid was taken up in CH2Cl2 and washed with water, which caused an insoluble precipitate to form. The solid was collected by filtration and washed with ethyl acetate to leave 2.5 g (87%) of intended product. 1H NMR (400 MHz, DMSO-d6): δ 12.74 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.25-7.36 (m, 5H), 5.26 (s, 2H), 2.46 (s, 3H). MS (ES) [m+H] calc'd for C18H14IN3O, 416; found 416.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1.Br[CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C=O)C.O>[CH3:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:15]=2)[N:11]=[C:10]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)[N:9]=1
Reactant: BrC1CCOCC1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(OC2CCOCC2)c1
Temperature: 140 °C

Procedure:
A mixture of Cs2CO3 (62.5 mg, 0.192 mmol), 3-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)phenol (Example 59; 40.0 mg, 0.096 mmol) and 4-bromotetrahydro-2H-pyran (21.7 uL, 0.192 mmol) in DMF (0.48 mL) was heated at 140° C. for 1 h under microwave irradiation. The mixture was diluted with H2O and extracted with 4:1 CHCl3:i-PrOH. The organic layer was dried over MgSO4 and concentrated under reduced pressure; the residue was dissolved in DMSO and purified using Prep-HPLC to furnish the title compound; MS (ES+) C24H22F3N5O4 requires: 501. found 502 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.29 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.28 (m, 1H), 6.89 (dd, J=8.1, 2.4 Hz, 1H), 6.80 (m, 2H), 5.41 (s, 2H), 4.47 (m, 1H), 3.95 (m, 2H), 3.57 (m, 2H), 2.54 (s, 3H), 2.01 (m, 2H), 1.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([C:14]#[C:15][CH3:16])=[CH:4][N:3]=1.CN(C=O)C>CCOC(C)=O.[Cu]I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH3:16])[N:8]([CH:9]([CH2:10][CH3:11])[CH2:12][CH3:13])[C:6]=2[N:7]=1
Reactant: CC#Cc1cnc(Cl)nc1NC(CC)CC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)n1c(C)cc2cnc(Cl)nc21
Temperature: 160 °C
Yield: 19.7 %

Procedure:
In a microwave vial is added (2-Chloro-5-prop-1-ynyl-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.22 g, 0.92 mmol), anhydrous DMF (3 ml), and CuI (53 mg, 0.27 mmol). The reaction is heated at 160° C. for 1 hr by employing microwave. The reaction mixture is diluted with EtOAc, washed with sat. NaHCO3 aqueous solution and water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, 1:4 EtOAC/Hexane) gives 43 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:8][C:5]1[CH:4]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=1
Reactant: Nc1ccc(F)cc1-c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(N=C=S)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-fluorobiphenyl (7.8 g) with thiophosgene (7.2 g) in a mixture of dioxan (15 ml) and water (60 ml) at ambient temperature for 2 hours yielded 5-fluoro-2-biphenylylisothiocyanate as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1
Yield: 68.9 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (333 mg, 1.1 mmol) and 3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H9) (314 mg, 1.0 mmol) according to the general procedure K. Obtained as a light yellow solid (374 mg).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][C:18](=[O:20])[C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=O.C(Cl)(=O)C([Cl:27])=O>C1C=CC=CC=1>[Cl:27][C:21]([C@H:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([C:18](=[O:20])[CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]1)[CH2:9][CH2:8]3)=[O:23]
Reactant: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)Cl)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 5α-androst-2-en-11-one 17β-carboxylic acid (6.3g.) in dry benzene (200 ml.) and oxalyl chloride (15.75 ml.) was refluxed for 1.5 hr. The mixture was evaporated to give 17β-chlorocarbonyl-5α-androst-2-en-11-one as a gum which shaken with 880 ammonia (100 ml.), benzene (32 ml.) and water (32 ml.) After 1 hr. the mixture was extracted with ether. The ethereal solution was washed (H2O), dried and evaporated to give a froth. Crystallisation from chloroform/petrol afforded the title compound (1.9g.); m.p. 92°-96°; [α]D + 95.5°, (c 0.75).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:39]([CH2:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:47](=[O:48])[CH2:46][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C(Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)NC(=O)COc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 26.2 %

Procedure:
To a stirring solution of 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanamine (0.431 mmol) and triethylamine (0.474 mmol, 1.1 eq.) in tetrahydrofuran (4 mL) at 0° C. was added phenoxyacetyl chloride (0.474 mmol, 1.1 eq.) and the resulting solution was stirred 5 min at 0° C. then warmed to room temperature and stirred 15 min. The reaction was quenched with saturated aqueous sodium bicarbonate solution (15 mL) and the resulting aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a white foam that was purified by column chromatography using 10% methanol/dichloromethane to give the final product as a clear oil (0.113 mmol, 26%). MS (ESI) m/z 570.3; HRMS: calcd for C33H32ClN3O4+H+, 570.21541; found (ESI, [M+H]+ Obs'd), 570.2155.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH2:17][OH:18])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.BrBr.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:16][CH2:17][O:18][CH:14]3[O:13][C:12](=[O:15])[CH:11]=[C:10]23)=[CH:4][CH:3]=1
Reactant: O=C1C=C(N(CCO)Cc2ccc(Cl)nc2)CO1
Agent: BrBr
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C2C(OCCN2Cc2ccc(Cl)nc2)O1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
At −78° C., a solution of 202 mg (0.75 mmol) of 4-[[(6-chloropyridin-3-yl)methyl](2-hydroxyethyl)-amino]furan-2(5H)-one (II-1) in 7 ml of tetrahydrofuran, also cooled to −78° C., is added to a mixture of 0.6 ml (1.50 mmol) of a 2.5M solution of n-butyllithium in hexane and 3 ml of tetrahydrofuran. After 20 minutes of stirring at −78° C., 39 μl (0.75 mmol) of bromine are added a little at a time, and stirring at −78° C. is continued for a further 30 min. After addition of saturated aqueous ammonium chloride solution, the mixture is warmed to room temperature and extracted with ethyl acetate. The combined organic phase is dried over magnesium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (95:5) gives 67 mg (32% of theory) of 1-[(6-chloropyridin-3-yl)methyl]-2,3-dihydro-1H-furo[2,3-b][1,4]oxazin-6(4aH)-one.