Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=[O:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:14]([Mg]Cl)[CH2:15][CH3:16]>O1CCCC1.CCOCC>[OH:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled stirred solution of methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (11.0 g, 59 mmol) in dry tetrahydrofuran (120 ml) under nitrogen was added a 2M solution of n-propylmagnesium chloride in ether (36 ml). The resulting mixture was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature with sting over 20 h, and quenched by dropwise addition of saturated aqueous ammonium chloride. The supernatant solution was decanted from the white solids and concentrated to dryness to give the title compound (11.5 g) as an oil.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH3:87][O:88][CH2:89][CH2:90][N:91]([CH3:96])[CH2:92][C:93](O)=[O:94]>>[CH3:87][O:88][CH2:89][CH2:90][N:91]([CH3:96])[CH2:92][C:93]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:94]
Reactant: COCCN(C)CC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN(C)CCOC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 38 %

Procedure:
The title compound was prepared in 38% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except N-(2-methoxyethyl)-N-methylglycine was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 659.6 (M+H)+, 2.41 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=7.9 Hz, 2H), 7.43 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 5.29 (d, J=5.8 Hz, 1H), 4.75 (s, 1H), 3.96 (br. s., 2H), 3.73 (t, J=4.7 Hz, 2H), 3.42 (s, 3H), 3.40 (br. s., 2H), 2.94 (s, 3H), 2.73-2.61 (m, 2H), 2.36 (dd, J=8.4, 12.1 Hz, 1H), 2.12 (dd, J=6.1, 17.1 Hz, 1H), 1.88 (t, J=11.6 Hz, 2H), 1.77 (d, J=11.6 Hz, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.70-1.65 (m, 1H), 1.58-1.30 (m, 11H), 1.25 (d, J=6.1 Hz, 1H), 1.18-1.10 (m, 2H), 1.09 (s, 3H), 1.02 (s, 3H), 1.01 (s, 3H), 0.94 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][C:31]1[N:36]=[C:35]([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:34]([N:45]([CH3:55])[S:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:48])=[O:47])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH:3]([CH3:7])[C:4]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([N:45]([S:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH3:55])=[C:35]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:36]=1)=[O:6])[CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(c1ccc(N)nc1C#Cc1ccccc1)S(=O)(=O)c1ccccc1
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)Nc1ccc(N(C)S(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (54 mg, 0.26 mmol) and N,N′-dicyclohexylcarbodiimide (27 mg, 0.13 mmol) in DCM (1.5 ml) is stirred at RT for 20 minutes. This mixture is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]-N-methylbenzenesulfonamide E5a (16 mg, 0.04 mmol) and DIPEA (9 μl; 0.05 mmol) in DCM (0.5 ml). After stirring for 4 days at 40° C. the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude product (22 mg) is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C@H:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.[CH3:36][O:37][CH:38]([O:43][CH3:44])[CH2:39][C:40](O)=[O:41].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C@H:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([Cl:25])[CH:16]=1)[CH3:13])[C:40](=[O:41])[CH2:39][CH:38]([O:43][CH3:44])[O:37][CH3:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CNCCCC(=O)OC(C)(C)C)Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: COC(CC(=O)O)OC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: COC(CC(=O)N(CCCC(=O)OC(C)(C)C)C[C@@H](C)Nc1ccc(C(F)(F)F)c(Cl)c1)OC
Temperature: 25 °C

Procedure:
A solution of 1.25 g (3.20 mmol) of 4-[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propylamino]-butyric acid tert-butyl ester (22% ee) in 25 ml CH2Cl2 was treated with a solution of 1.00 g (3.80 mmol) of 2-chloro-1-methylpyridinium iodide and 0.51 g (3.80 mmol) of 3,3-dimethoxy-propionic acid (synthesized from methyl 3,3-dimethoxy-propionate by hydrolysis with LiOH) in 5 ml of CH2Cl2. The suspension was cooled and treated at 0° C. with 1.89 ml (7.90 mmol) of tributylamine. The reaction was naturally warmed to RT over night. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with 10% aq. KHSO4 solution (2×), sat. aq. NaHCO3 solution, 10% aq. NaCl solution and dried over Na2SO4 to yield 1.68 g (quantitative) of the title compound as a 61:39 mixture of the (R) and (S) diastereomers as light brown oil. MS: 511.22 (MH+, Cl).
Reaction SMILES: [CH3:1][C:2]12[O:11][CH:8]([CH2:9][CH2:10]1)[CH:7]1[CH:3]2[C:4](=[O:13])[CH2:5][C:6]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl>[Cl:15][C:6]1[CH:7]2[CH:3]([C:2]3([CH3:1])[O:11][CH:8]2[CH2:9][CH2:10]3)[C:4](=[O:13])[CH:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC12CCC(O1)C1C(=O)CC(=O)C12
Solvent: ClC(Cl)Cl
Product: CC12CCC(O1)C1C(Cl)=CC(=O)C12

Procedure:
To a solution of 1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (3 g, 16.6 mmol) in chloroform (8 ml) is added PCl5 portionwise. The reaction mixture is stirred and heated at reflux for 5 hours. The reaction mixture is evaporated to dryness The crude product is purified by flash chromatography on silica gel to give 5-chloro-1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (1.39 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:18])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Heat a mixture of 4′-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g, 39.12 mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120.mL) for 14 h at reflux. Cool to ambient temperature and wash sequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 9:1) to provide the title compound as oil (5.191 g, 65%). GC-MS m/z: 213 (M+).
Reaction SMILES: C([NH:9][C:10]1[C:11]2[N:18]=[N:17][N:16]([CH:19]3[O:23][CH:22]([CH:24]=[CH:25][P:26](=[O:29])([OH:28])[OH:27])[CH:21]([OH:30])[CH:20]3[OH:31])[C:12]=2[N:13]=[CH:14][N:15]=1)(=O)C1C=CC=CC=1>[NH4+].[OH-]>[NH2:9][C:10]1[C:11]2[N:18]=[N:17][N:16]([CH:19]3[O:23][CH:22]([CH2:24][CH2:25][P:26](=[O:27])([OH:28])[OH:29])[CH:21]([OH:30])[CH:20]3[OH:31])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C(Nc1ncnc2c1nnn2C1OC(C=CP(=O)(O)O)C(O)C1O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ncnc2c1nnn2C1OC(CCP(=O)(O)O)C(O)C1O
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Compound 6.6 (50 mg, 0.11 mmol) was dissolved in 15 mL NH4OH and stirred under N2 for overnight. The mixture was concentrated under reduced pressure. The residue was subjected to reverse phase HPLC eluting with 0-25% CH3CN in water to yield product 6.7 (34 mg, 89% yield). 1HNMR (300 MHz, D2O) δ 4.47-4.51 (m, 1H), 4.59-4.61 (m, 1H), 4.96-4.99 (m, 1H), 5.85 (t, 1H, J=17.1), 6.22-6.37 (m, 2H), 8.20 (s, 1H). 31P NMR: 10.98 ppm. LRMS (ESI) MH+ C10H13N6O6P requires 345.1. Found 345.8.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].Br[CH2:23][C:24]#[C:25][CH3:26].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[OH:4][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)([C:2]([F:20])([F:1])[F:21])[C:25]([CH3:26])=[C:24]=[CH2:23]
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Reactant: CC#CCBr
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C=C(C)C(O)(c1nc2cc(C#N)c(C(F)(F)F)cc2[nH]1)C(F)(F)F

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.31 g; 0.94 mmol), 1-bromo-2-butyne (0.85 mL; 9.4 mmol) and indium (1.09 g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL) and stirred vigorously overnight. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].C[O:24][CH:25]1[CH:29]([CH:30]=O)[CH2:28][CH:27](OC)O1>C(O)(=O)C>[CH:25]([C:29]1[CH:28]=[CH:27][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]3=[O:22])[CH:30]=1)=[O:24]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc2c1=O
Yield: 65 %

Procedure:
To a solution of 100 mg (0.296 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 2 ml acetic acid is added a solution of 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde in 1 ml acetic acid and the mixture is refluxed for 3 hours. The solvent is removed by rotavapor evaporation and the brown oil is purified by reversed phase chromatography (C18) with an acetonitril-water gradient to give 80 mg (65%) of N-[6-(3-formyl-pyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a black solid. MS (ES+): m/e =417 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:42]([O:44]CCCC)=[CH2:43].C([O-])(O)=O.[Na+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:8][C:5]1[CH:4]=[C:3]([C:9]([F:12])([F:11])[F:10])[C:2]([C:42](=[O:44])[CH3:43])=[N:7][CH:6]=1
Reactant: C=COCCCC
Reactant: Nc1cnc(Cl)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CO
Product: CC(=O)c1ncc(N)cc1C(F)(F)F
Reaction time: 1 h

Procedure:
Heat a mixture of 6-chloro-5-trifluoromethyl-pyridin-3-ylamine (985 mg, 5.0 mmol), palladium acetate (20 mg), DPPP (60 mg), butyl vinyl ether (1.5 g, 15 mmol) and NaHCO3 (840 mg, 10 mmol) in MeOH (10 mL) at 130° C. for 18 hours. Cool, filter and wash the solid with MeOH. Add 6M hydrochloric acid (5 mL), stir for 1 hour and evaporate the volatiles. Dissolve the residue in EtOAc (50 mL) and wash with saturated NaHCO3(aq) (50 mL) and brine (50 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[Cl-].[CH:8]([P+:11]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])OC=C(Cl)Cl)([CH3:10])[CH3:9]>CCOCC>[CH:8]([P:11]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:10])[CH3:9].[O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: CC(C)[P+](OC=C(Cl)Cl)(C(C)C)C(C)C
Agent: O=CC(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)P(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
To chloral (200 ml.) heated to 60°C. under nitrogen was added 11.5 g. of triisopropyldichlorovinyloxyphosphonium chloride (from C-3 above). The clear solution was held overnight under nitrogen at 60°C. and then poured into 400 ml. of dry ether. The oil which first separated became crystalline on standing at room temperature. The solid was collected under nitrogen and recrystallized by dissolution in 80 ml. of dichloromethane and dilution with 400 ml. of dry ether. The crystalline 3/1 chloral/triisopropylphosphine reaction product was collected and dried under dry nitrogen.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([C:16]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:24]3[C@@H:20]([CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23]3)[C@@:19]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])(O)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[C:10]1([C:16]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:24]3[C@@H:20]([CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23]3)[C@:19]([F:7])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Solvent: ClCCl
Product: COc1ccccc1[C@]1(F)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 3 h

Procedure:
A solution of 4.3 cm3 of diethylaminosulphur trifluoride in 20 cm3 of dry methylene chloride is added dropwise to a solution, cooled to 0° C., of 6.48 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-tert-butoxycarbonyl-perhydroisoindol-4-ol in 70 cm3 of dry methylene chloride. The reaction mixture is stirred at this temperature for 3 hours, washed with 100 cm3 of an aqueous saturated solution of sodium bicarbonate and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 26 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (95/5 by volume) and collecting fractions of 50 cm3. Fractions 34 to 63 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2.2 g of (3aS,4S,7aS)-7,7-diphenyl-4-fluoro-4-(2-methoxyphenyl)-2-tert-butoxycarbonyl-perhydroisoindole are obtained in the form of a white foam.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:22]=[CH:21][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].N>[Rh]>[NH2:2][CH2:1][C:3]([C:6]1[CH:22]=[CH:21][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1)([CH3:4])[CH3:5]
Reactant: COc1ccc(NC(=O)c2ccc(C(C)(C)C#N)cc2)cc1
Agent: [Rh]
Agent: N
Product: COc1ccc(NC(=O)c2ccc(C(C)(C)CN)cc2)cc1

Procedure:
2 g. 4-(1-Cyano-1-methylethyl)-N-(4-methoxyphenyl)-benzamide (Example 22) in 100 ml. 10% ethanolic ammonia solution are hydrogenated in the presence of 1 g. 5% rhodium on aluminium oxide for 24 hours at 5 bar. The reaction mixture is filtered with suction, the filtrate is evaporated to dryness and the residue is recrystallised from ethanol. There is obtained 0.68 g. (34% of theory) of the title compound in the form of colourless crystals; m.p. 139°-140° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[F:19])[N:12]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:10]=2[CH3:27])=[CH:6][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:4][N:3]=1.[F:34][CH:35]([F:52])[O:36][C:37]1[CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:41][CH:42]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:34][CH:35]([F:52])[O:36][C:37]1[CH:42]=[C:41]([C:2]2[C:7]([NH:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=4[F:19])[N:12]=[C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:10]=3[CH3:27])=[CH:6][C:5]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:4][N:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1Cl
Reactant: CC1(C)OB(c2cccc(OC(F)F)c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1-c1cccc(OC(F)F)c1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-chloro-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine (49.1 mg, 0.10 mmol), 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (56.9 mg, 0.21 mmol), tricyclohexylphosphine (5.1 mg, 0.018 mmol), and tris(dibenzylideneacetone)dipalladium (0) (8.9 mg, 9.7 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.21 mL, 0.27 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a film that was triturated with MeOH to afford a yellow solid as N-(2-(3-(difluoromethoxy)phenyl)-5-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.69 (1H, d, J=4.9 Hz), 8.06 (2H, m), 7.91 (1H, d, J=3.7 Hz), 7.80 (1H, d, J=7.8 Hz), 7.59 (2H, m), 7.47 (2H, m), 7.36 (4H, m), 6.54 (1H, d, J=2.4 Hz), 3.76 (4H, m), 3.15 (4H, m), 2.14 (3H, s). Mass Spectrum (pos.) m/e: 576.1 (M+1).
Reaction SMILES: O[C:2]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:2]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])=[CH2:3]
Reactant: Cn1c(C(C)(C)O)cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 23.5 %

Procedure:
4.0 g of 2-(1-hydroxy-1-methylethyl)-1-methylindole was dissolved in 80 ml of toluene. Thereto was added 200 mg of p-toluenesulfonic acid monohydrate. The mixture was azeotropically refluxed for 2 hours. The reaction mixture was cooled to room temperature, washed with an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/toluene=1/0 to 20/1) to obtain 850 mg (yield: 24%) of 2-isopropenyl-1-methylindole as a light yellow oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]
Reactant: O=C(CBr)c1ccc(Cl)cn1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-5-chloropyridine*.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[CH2:8]([NH:10][C:11](=[O:29])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)[CH3:13])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:8]([NH:10][C:11](=[O:29])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([O:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[CH3:13])[CH3:9]
Reactant: OCc1ccco1
Reactant: CCNC(=O)C(C)c1ccc(C#Cc2ccc(O)cc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCNC(=O)C(C)c1ccc(C#Cc2ccc(OCc3ccco3)cc2)cc1
Temperature: 0 °C

Procedure:
To 0.015 g (0.15 mmol) furan-2-ylmethanol in 0.75 mL THF are added 0.03 g (0.10 mmol) N-Ethyl-2-[4-(4-hydroxy-phenylethynyl)-phenyl]-propionamide (XVIII.2) and 40 mg polymer-bound triphenylphosphine (3 mmol/g resin). The mixture is cooled to 0° C. and 0.03 g (0.15 mmol) di-tert-butyl azodicarboxylate dissolved in 0.5 mL THF are added. The mixture is stirred over night at rt. After that time additional 0.03 g (0.15 mmol) di-tert-butyl azodicarboxylate dissolved in 0.5 mL THF are added and stirring is continued over night. Subsequently the mixture is filtered (Alox), washed (DMF/MeOH 9:1) and concentrated. The residue is dissolved in DMF and the desired product was purified using RP-HPLC (narrow gradient, water/MeOH+0.1% TFA).