Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[F:27][C:28]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([CH3:39])[C:29]=1[C:30](Cl)=[O:31].Cl>C1COCC1>[F:27][C:28]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([CH3:39])[C:29]=1[C:30]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[O:31]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
A solution of 8.0 g (60.5 mmol) of malonic acid monoethylester, bipyridyl (catalytic) and 200 mL of dry THF was cooled to -35° C. under argon, treated with 32 mL of 1.9M n-butyllithium (60.8 mmol), and warmed to -5° C. To this suspension was added another 32 mL of 1.9M n-butyllithium until a pale pink color persisted for 10 minutes. The mixture was cooled to -78° C. To this mixture was added a solution of 6.3 g (30.2 mmol) of 2,4,5-trifluoro-6-methylbenzoyl chloride in 75 mL of dry THF, and the reaction mixture was stirred at -78° C. for 1 hour. The solution was then warmed to -35° C., poured onto a mixture of ice and 1N hydrochloric acid (70 mL), and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, 3M hydrochloric acid, and water, and was stirred over magnesium sulfate. Concentration gave an orange oil which was chromatographed on silica gel (E. Merck 230-400 Mesh), eluting with 80:20 chloroform:ethyl acetate, to give 7.2 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]([CH2:25][C:26]3[O:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:27]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(N3CCCN(C(=O)OCC)CC3)nc3ccccc32)o1
Reaction time: 72 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (10 mmol) and sodium hydride (10 mmol) in dimethylformamide (20 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (10 mmol) and stir. After 3 days, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=O)=[CH:25]2.N1CCCCC1>C(O)C>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:25]2
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
A mixture of 5-phenyl-2-oxindole (41 mg, 0.2 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (46 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 58 mg (68%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5](O)=O)[CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:12]=[C:13]([O:18]C)[CH:14]=[CH:15][C:16]=1[NH2:17]>>[OH:18][C:13]1[CH:14]=[CH:15][C:16]2[NH:17][C:5]([CH:4]3[CH2:8][CH2:9][NH:1][CH2:2][CH2:3]3)=[N:10][C:11]=2[CH:12]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C(O)C1CCNCC1
Product: Oc1ccc2[nH]c(C3CCNCC3)nc2c1

Procedure:
The title compound was prepared from isonipecotic acid and 3,4 diamino anisole using the method described in Description 14. MH+ 218.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[C:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:30][CH:31]1[O:33][CH2:32]1)(=O)=O>O>[O:33]1[CH2:32][CH:31]1[CH2:30][O:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[C:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18]
Reactant: O=C1OCCC1=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCCC1=Cc1ccccc1OCC1CO1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Dimethylformamide (30 ml) and potassium carbonate (4.4 g) were added to α-(2′-hydroxybenzylidene)-γ-butyrolactone (3 g), and a racemic compound of glycidyl nosylate (3.4 g) was added. The mixture was stirred at 50° C. for 3 hr. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give oily α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (3.2 g). This compound (0.4 g) was reacted in methanol with 4-(naphthalen-2-yl)piperidine (0.5 g) in the same manner as in Example 307 to give the title compound, melting point 127–128° C.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 74 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.037 ml of methanesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of methanesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone to give 113.2 mg (yield 74%) of the title compound.
Reaction SMILES: [CH2:1]([S:7]([OH:10])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][C:12]([N:14]([OH:49])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH2:23][CH2:24][C:25]([N:27]([OH:48])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([CH2:36][CH2:37][C:38]([N:40]([OH:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[O:39])=[O:35])=[O:26])=[O:22])=[O:13]>>[CH2:1]([S:7]([O-:10])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][C:12]([N:14]([OH:49])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH2:23][CH2:24][C:25]([N:27]([OH:48])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([CH2:36][CH2:37][C:38]([N:40]([OH:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[O:39])=[O:35])=[O:26])=[O:22])=[O:13]
Reactant: CCCCCCS(=O)(=O)O
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Product: CCCCCCS(=O)(=O)[O-]

Procedure:
Following a procedure analogous to that of Example 1, hexane-1-sulphonic acid and desferrioxamine-B are reacted to give the hexane-1-sulphonate salt of desferrioxamine-B. Mp 138° C. C31H62O11N6S Calcd C: 51.22%, H: 8.60%, N: 11.56%, S: 4.41%; Found C: 51.04%, H: 8.50%, N: 11.40%, S: 4.19%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[NH:30][N:29]=2)[C:24]([C:36]#[C:37][Si](C)(C)C)=[CH:23][N:22]=1.C1(C2NN=C(NC3C(C#C)=CN=C(C4C=C(S(N)(=O)=O)C=CC=4)N=3)C=2)CC1>[Pd]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:21]2[N:26]=[C:25]([NH:27][C:28]3[NH:29][N:30]=[C:31]([CH:33]4[CH2:35][CH2:34]4)[CH:32]=3)[C:24]([C:36]#[CH:37])=[CH:23][N:22]=2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(N)=O)c2)OC1(C)C
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Pd]
Agent: C#Cc1cnc(-c2cccc(S(N)(=O)=O)c2)nc1Nc1cc(C2CC2)[nH]n1
Product: C#Cc1cnc(-c2ccc(Cl)c(C(N)=O)c2)nc1Nc1cc(C2CC2)n[nH]1
Yield: 13 %

Procedure:
2-chloro-5-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynylpyrimidin-2-yl) benzamide (Compound 128) (40 mg, 13%) was prepared from 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine using the same Pd cataliysed condition as described in Compound 110. LC-MS (m/z)=378.9 [M+H1H NMR (400 MHz, DMSO-d6): δ 0.75-0.76 (m, 2H), 0.98-0.99 (m, 2H), 1.89-1.97 (m, 1H), 4.87 (s, 1H), 6.41 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 8.05 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H), 8.58 (s, 1H), 8.75 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C>[Br:11][CH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[CH:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)cc(C#N)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: N#Cc1cc(F)cc(CBr)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
3-Fluoro-5-methylbenzonitrile (Hognda Trading; 100 g, 0.74 mol) was taken in acetonitrile (1 L) at 25° C. under nitrogen atmosphere. N-Bromosuccinimide (105 g, 0.59 mol) and AIBN (2.4 g, 0.014 mol) were added and the reaction mixture was heated at 70° C. for 1 h 20 minutes. The reaction mixture was cooled to 25° C. and concentrated. The residue was diluted, cooled to 0-5° C. and stirred for 15 minutes at the same temperature. The precipitated succinimide was filtered and the filtrate was concentrated to get crude product as yellow oil (90 g). It was taken in petroleum ether (200 mL) and cooled to −20° C. stirred for 30 minutes. The precipitated solids were filtered and dried to get the title product as white solid. 1H NMR (DMSO-d6; 400 MHz): δ 7.83 (m, 2H), 7.73 (m, 1H), 4.72 (s, 2H). HPLC (Method A) Rt: 4.17 min (Purity: 99.4%).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(#N)C>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1c2nc(C3=CC4CN(S(C)(=O)=O)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reaction time: 0.17 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (24-2, 40 mg, 0.11 mmol, 1.0 equiv) was added to anhydrous acetonitrile (1.0 mL) followed by the sequential addition of DIPEA (55 μL, 0.31 mmol, 3.0 equiv) and methanesulfonyl chloride (12 μL, 0.16 mmol, 1.5 equiv). After 10 min at RT, LCMS showed complete consumption of starting material. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 26-1 as a white solid. MS ink (M+H): calculated=461.1123; observed=461.1129.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:52])[C:32]([C:50]#[N:51])=[CH:33][C:34]([N:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)([CH3:36])[CH3:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:33][C:34]([CH3:36])([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH3:35])[C:50]#[N:51])=[O:52])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=C(C#N)C(=O)N2CCC[C@@H](n3nc(-c4ccc(Oc5ccccc5)cc4F)c4c(N)ncnc43)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CCNCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a 30-mL round-bottom flask cooled to 0° C., was placed dichloromethane (8 mL), (R)-tert-butyl 4-(5-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate (170 mg, 0.24 mmol, 1.00 equiv), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum and the residue was dissolved in DCM. The resulting mixture was washed with 20 mL of aqueous potassium carbonate. The organic layer was dried over anhydrous sodium sulfate, concentrated to give the crude product. The crude product was purified by re-crystallization from ether. This resulted in 27 mg of 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile as a light yellow solid. LCMS (ESI, pos. ion) m/z: 610 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=1)[CH2:10][C:9]([CH3:20])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39](Cl)([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27].O>CCOCC.C([Cu])#N>[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39]([CH:8]2[C:7]3[C:11](=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:13]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)[CH:10]=[C:9]2[CH3:20])([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Reactant: CC1=Cc2cc(C(C)(C)C)cc(-c3ccccc3)c2C1
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccccc3)cc(C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 14.5 g (55.4 mmol) of 5-tert-butyl-2-methyl-7-phenyl-1H-indene in 400 ml of ether cooled to −78° C., 22.2 ml (55.5 mmol) of 2.5 M nBuLi in hexanes was added. This mixture was stirred overnight at room temperature, then cooled to −78° C., and 200 mg (2.23 mmol) of CuCN was added. The resulting mixture was stirred for 30 min at −20° C., then cooled to −78° C., and a solution of 21.2 g (55.4 mmol) of (6-tert-butyl-5-methoxy-2-methyl-4-phenyl-1H-inden-1-yl)(chloro)dimethylsilane in 200 ml of ether was added. This mixture was stirred overnight at room temperature, then 1 ml of water was added. The obtained mixture was passed through a short layer of silica gel 60 (40-63 um), the elute was evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um; eluent: hexanes-dichloromethane=10:1, vol., then 3:1, vol.). This procedure gave 24.5 g (72%) of yellowish glassy solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=[O:17].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[N:31]O)[CH2:26][CH2:25]2>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:17])[NH:31][CH2:26][CH2:25]2
Reactant: COc1ccc2c(c1)CCC2=NO
Reactant: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorous pentoxide (1.0 g, 7.1 mmol) is added all at once to methanesulfonic acid (10 g, 104.1 mmol) and stirred for 3 hours at room temperature. 5-Methoxy-1-indanone oxime (100 mg, 0.53 mmol) is added in portions, with each portion allowed to dissolve completely before the next is added. The stirred reaction mixture is heated at 100° for 1.5 hours. The reaction is quenched by the addition of saturated sodium bicarbonate (10 ml) and extracted with 3×5 ml dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to yield the 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline. Treatment with boron tribromide (see example 1 ) yields 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3].C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:25][CH:26]([OH:27])[C:34]([F:37])([F:36])[F:35])[CH2:28][CH3:29])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)C(F)(F)F)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of (S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal (100 mg, 0.218 mmol; Example 130, Step A) in THF (2.2 mL) was added trimethyl(trifluoromethyl)silane (97 μL, 0.66 mmol) at 0° C. and the reaction was stirred for 5 min. Then 1 M TBAF in THF (327 μL, 0.327 mmol) was added slowly at 0° C. After being stirred at 0° C. for 40 min, the reaction was quenched (sat. aq. NaCl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 13% and 23% EtOAc/Hex) provided the title compound as a mixture of two diastereomers.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([OH:21])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:2]1.Cl.[F:23][C:24]1([F:32])[CH2:28][NH:27][C@@H:26]([C:29]([NH2:31])=[O:30])[CH2:25]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([N:27]3[CH2:28][C:24]([F:32])([F:23])[CH2:25][C@@H:26]3[C:29]([NH2:31])=[O:30])=[O:21])=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:17])([F:18])[C:13]([F:14])([F:16])[F:15])[CH2:2][CH2:3]1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Agent: Cl
Product: NC(=O)[C@H]1CC(F)(F)CN1C(=O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (30 mg, 96 μmol) and (2R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 1315053-41-8; 19.8 mg, 106 μmol) as starting materials and isolated (38 mg, 89%) as white solid; LC-MS (UV peak area, ESI) 97%, 444.1155 [MH+].
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Cl:9]Cl>>[CH3:1][NH:2][C:3](=[O:8])[CH:4]([Cl:9])[C:5]([CH3:7])=[O:6]
Reactant: ClCl
Reactant: CNC(=O)CC(C)=O
Product: CNC(=O)C(Cl)C(C)=O
Yield: 97.4 %

Procedure:
Altogether, the aqueous phase was subjected to chlorination five times. A total of 492 parts by weight of N-methylacetoacetamide (MMAA) of 99.5% strength, and 283.5 parts by weight of chlorine were used, and altogether 588.6 parts by weight of 97.4% N-methyl-α-chloracetoacetamide (MMCAA) were obtained, that is, 96.8% of the theoretical yield, calculated on reacted MMAA.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]([NH:8][C:9](=[O:18])[O:10][CH2:11]C1C=CC=CC=1)([CH3:7])CO.[H-].[Na+].CC(O)=O>C1COCC1>[CH3:7][C:4]1([CH2:3][C:2]([F:1])([F:19])[F:20])[CH2:11][O:10][C:9](=[O:18])[NH:8]1
Reactant: CC(CO)(CC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(CC(F)(F)F)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A solution of benzyl 4,4,4-trifluoro-1-hydroxy-2-methylbutan-2-ylcarbamate (830 mg, 2.85 mmol) in THF (55 ml) was cooled to 0° C., and 60% NaH in mineral oil (143 mg, 3.6 mmol) added in one portion. The suspension was stirred for 30 min, then warmed to RT and stirred for 24 h. AcOH (200 ul) added to quench the reaction, and the solution was concentrated in vacuo. The residue was purified by flash chromatography (5% to 20% CH3CN in DCM) to afford the title compound as a white solid (405 mg). 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 3H), 2.43-2.53 (m, 2H), 4.10 (d, J=8.8 Hz, 1H), 4.28 (d, J=8.8 Hz, 1H), 6.84 (s, 1H). 19F NMR (CDCl3, 376 MHz) δ −61.3 (t, J=10.9 Hz). 13C NMR (CDCl3, 100 MHz) δ 25.3, 43.0 (q, J=27.2 Hz), 55.0, 75.4, 125 (q, J=277.8 Hz), 158.7. LRMS (ESI/APCI): 184 [M+H]+, 225 [M+H+CH3CN]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.C(O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: COc1ccccc1CNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccccc1CNc1ccccc1N
Yield: 92.3 %

Procedure:
A solution of 32 g (0.13 mole) of (2-methoxy-benzyl)-(2-nitro-phenyl)-amine (1) and 3.2 g Pd/C in 200 mL of 1:1 ethyl acetate:ethanol is treated at 40 psi of hydrogen for 1 hour. The reaction mixture is then filtered through celite and washed with 200 mL of ethanol. The solvent is then removed in vacuo to afford 28.2 g (0.12 mole, 92%) of N-(2-Methoxy-benzyl)-benzene-1,2-diamine (2).