Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[C:13][Si](C)(C)C)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[CH:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Cl)cc1C(=O)OC
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of methyl 5-chloro-2-[2-(trimethylsilyl)ethynyl]benzoate (10 g, 37.5 mmol) in Methanol (150 ml) was added K2CO3 (10.36 g, 75 mmol) at room temperature and in air. The reaction mixture was stirred for 1 hour before being concentrated under reduced pressure. The residue was dissolved in deionized water (50 ml) and EtOAc (50 ml). The phases were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 9:1 Heptane:EtOAc) to give 5.75 g (55.2%) of methyl 5-chloro-2-ethynylbenzoate as an orange oil that solidified upon standing. This material contained 30% of ethyl ester which was suitable for use without any further purification. LC-MS 38%, 1.98 min (3 minute LC-MS method), m/z=195.0/196.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.93 (d, J=2.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.45 (dd, J=8.3, 2.3 Hz, 1H), 3.94 (s, 3H), 3.43 (s, 1H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O.Cl.[NH2:24][C:25]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[NH:26].[O-]CC.[Na+]>C(O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:24]=[C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]4)[N:26]=2)[CH:13]=[CH:12][O:11]3)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=N)N)CC1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc(-c3c(-c4ccc(F)cc4)nc4occn34)n2)CC1
Yield: 65.3 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]prop-2-en-1-one (4.24 g, 14.2 mmol) and tert-butyl 4-{[amino(imino)methyl]amino}-piperidine-1-carboxylate hydrochloride (5.92 g, 21.2 mmol) was diluted with 40 ml of absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of sodium ethoxide in ethanol (7.2 ml) to form a reaction mixture. The reaction mixture was heated to reflux for 15 hours. Volatiles were removed in vacuo and the residue was taken up in 200 ml of ethyl acetate, washed twice with 100 ml each of water, and then with a saturated sodium chloride solution (100 ml). The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo, to give a brown solid. The product was purified by flash chromatography on silica gel (gradient 50%-75% ethyl acetate/hexanes) to yield 4.436 g of a tan solid (65%). M.p.=175° C.; 300 MHz 1H NMR (CDCl3) δ: 8.06 (s, 1H), 8.04 (s, 1H), 7.65-7.60 (m, 2H), 7.48 (d, J=1.6 Hz, 1H), 7.17-7.13 (m, 2H), 6.52 (d, J=5.6 Hz, 1H), 5.1 (br. s, 1H), 4.2-3.9 (m, 3H), 2.2-2.0 9M, 2H), 16.-1.4 (m, 4H), 1.48 (s, 9H). LCMS: 479 [M+H]; calc. for C25H27FN6O3.0.25H2O: C, 62.11; H, 5.74; N, 17.39. Found C, 62.43; H, 5.37; N, 17.35.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:3]=12.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[CH2:15]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:24][CH2:23][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[C:3]2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:16]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3ccccc3nc21
Reaction time: 48 h
Yield: 90.5 %

Procedure:
To a mixture of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoline (10 g, 0.043 mol) and DMSO (75 ml) was added cyclohexanemethylamine (10.75 g, 0.095 mol). The reaction mixture was refluxed for about four hours, then was allowed to stand for about 2 days. About 40-50 ml of the DMSO was removed in vacuo and the residue was pured into ice-water. A precipitate formed which was collected by filtration, washed with water and dried. The PG,13 solid precipitate was dissolved in CH2Cl2, washed with water, then brine and was then dried over MgSO4. The solvent was filtered and concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/cyclohexane (3/7) followed by recrystallization from hexane to afford 12 g (90.2%) of 1-ethyl-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as light yellow crystals, m.p. 161°-163° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][NH:24][CH2:23][CH2:22][O:21][CH3:20])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: COCCN
Product: COCCNCc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of Example 15 and (2-methoxy-ethyl)-amine.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:11][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:13])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
2-Amino-4-methyl-3-nitropyridine (120 g, 0.78 mol) was suspended in water (1.6 L), a concentrated sulfuric acid (120 mL) was added dropwise, and the clear yellow solution was cooled to 0° C. in an ice bath. Sodium nitrite (98 g, 1.42 mol) dissolved in water (250 mL) was added slowly bellow the liquid surface of the reaction solution through a long stem funnel. The reaction mixture was stirred at room temperature for 2 h and was boiled up until no further emission of a brown gas was observed. The reaction solution was cooled, filtered, and dried to obtain the title compound (yield 91.6%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([O:25][CH3:26])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([O:25][CH3:26])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: COC1(C)CCN(c2c(Br)c(C)nc(C)c2[C@H](O)C(=O)OC(C)C)CC1
Solvent: ClCCl
Product: COC1(C)CCN(c2c(Br)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 164.6 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (1.45 g, 3.38 mmol) and 0.32 mL of 70% HClO4 in DCM (30 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 48 h in a pressure sealed vessel. The reaction was then diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-methoxy-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 1.35 g (82%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 6.18 (br. s, 1H), 4.93-4.89 (m, 1H), 4.01 (br. s, 1H), 3.46 (t, J=11.0 Hz 1H), 3.37-3.28 (m, 2H), 3.15 (s, 3H), 2.52 (s, 3H), 2.42 (s, 3H), 1.79-1.51 (series m, 4H), 1.16-1.14 (m, 15H), 1.07 (d, J=6.2 Hz, 3H). UPLC (M+H)=487.4.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH:4]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:25]=1)[O:5][P:6]([C@@H:9]([NH:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7].[Li+].[OH-].Cl>CO.O>[C:36]([O:35][C:33]([N:32]=[C:31]([NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[NH:30][C:26]1[CH:25]=[C:24]([CH:4]([O:5][P:6]([C@@H:9]([NH:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:15])=[O:16])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7])[C:3]([OH:48])=[O:2])[CH:29]=[CH:28][CH:27]=1)=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)C(OP(=O)(O)[C@@H](NS(=O)(=O)Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[C@H](NS(=O)(=O)Cc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 6 h

Procedure:
To a slurry of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester (0.53 mmol) in 6 mL of methanol and 3 mL of H2O was added LiOH (124.3 mg, 5.3 mmol). After stirring for 6 hours, the solution was acidified to pH 2 with concentrated HCl and extracted with methylene chloride (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid as a yellow oil that was used without further purification in the following step.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]([CH3:30])=[CH:27][CH:28]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:28][CH:27]=[C:26]([CH3:30])[CH3:25])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CC(C)=CC=O
Solvent: CC(=O)N(C)C
Product: CC(C)=CC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 80.4 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-methylbut-2-enal (0.5 g, 5.9 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.093 g, 80%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: Sc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
2-mercaptopyridine (10 g) was dissolved in DMF (100 ml), 60% sodium hydride (3.6 g) was added to the mixture at 0° C., and then, the mixture was stirred for 15 minutes at room temperature. 4-fluoronitrobenzene (9.75 g) was added dropwise to the mixture at 0° C. and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added, and the precipitated crystals were collected by filtration, and washed with hexane/diethylether, to give 2-[(4-nitrophenyl)sulfanyl]pyridine (12.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C@:19]([CH2:35][OH:36])([C:31]([O:33][CH3:34])=[O:32])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.N1C=CN=C1.[Si:42](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CN(C=O)C>[CH3:46][C:45]([Si:42]([CH3:44])([CH3:43])[O:36][CH2:35][C@@:19]1([C:31]([O:33][CH3:34])=[O:32])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([CH3:48])[CH3:47]
Reactant: COC(=O)[C@]1(CO)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@]1(CO[Si](C)(C)C(C)(C)C)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Reaction time: 36 h
Yield: 74 %

Procedure:
To a solution of 2-methyl 1-(phenylmethyl) (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D71, 200 mg, 0.4 mmol) and imidazole (60 mg, 0.88 mmol) in dry DMF (1 ml) was added tert-butyl dimethylsilyl chloride and the mixture was stirred for 36 hours. The reaction was quenched with brine, diluted with water and extracted with ethyl acetate. The organic layer was washed with ice cold brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (1:0 to 9:1) to afford the title compound as a colourless oil (180 mg, 74%); Rt (HPLC): 8.50 min; MS: (ES/+) m/z: 608 [MH]+ C34H42FNO6Si requires 607.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]S([O-])(=O)=O)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.[C-]#[N:37].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:37])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCCS(=O)(=O)[O-])c23)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCC#N)c23)cc1

Procedure:
Stir a mixture of 400 mg (approx. 0.80 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidin-4-yl]amino}hexyl-methanesulphonate and 526 mg (8.1 mmol) potassium cyanide in 20 ml DMF overnight at 80° C. After cooling, dilute with ethyl acetate and wash with water and saturated sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). 249 mg (72% of theor.) of the title compound is obtained as a yellowish oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23]Br>>[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH2:23][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Fc1ccc(F)c(CBr)c1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cc(F)ccc2F)c(=O)[nH]c1=O
Yield: 47.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 47.9%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]1[C:22](OC)=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[BH4-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]1[CH2:22][OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1O[Si](C)(C)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 1-tert-butyl 3-methyl 4-(tert-butyldimethylsilyloxy)piperidine-1,3 dicarboxylate from step A in THF (100 mL) was cooled at 0° C. and then LiBH4 (1.10 g, 50 mmol) was added in. After stirring for 2 hours as the solution was warmed to room temperature, the pH value was adjusted to 4 with 1M citric acid. After removal of the volatiles in vacuo, the product was extracted in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate. Upon filtering and removal of the volatiles in vacuo, tert-butyl 4-(tert-butyldimethylsilyloxy)-3 (hydroxymethyl)piperidine-1-carboxylate was obtained (8.82 g, 100% yield), which was used directly in the next step. MS (m/z): 246 (M-Boc+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[S:13]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14]1>>[C:9]1([C@H:18]2[C@H:18]([C:15]3[CH:16]=[CH:17][S:13][CH:14]=3)[C:19](=[O:20])[NH:21][C:19]2=[O:20])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:16][CH2:15][CH2:14][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccsc1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccsc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(thiophen-3-yl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with thiophen-3-ylacetamide. Yield 50.3 mg, 15.0%. 1H NMR (DMSO-d6) 400 MHz δ: 11.50 (s, 1H), 7.52 (m, 1H), 7.49 (m, 1H), 7.35 (s, 1H), 7.21 (dd, 1H, J=4.0 1.2 Hz), 7.16 (d, 1H, 7.6 Hz), 6.89 (d, 1H, J=4.4 Hz), 6.85 (t, 1H, J=6.8 Hz), 4.56 (d, 1H, J=7.2 Hz), 4.41 (d, 1H, J=7.2 Hz), 4.10 (t, 2H, J=6.0 Hz), 2.90 (t, 2H, J=6.0 Hz), 2.10 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:36][C:37]1[C:69]([C:70]([F:73])([F:72])[F:71])=[CH:68][CH:67]=[CH:66][C:38]=1[CH2:39][N:40]([CH2:52][CH:53]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:41][CH2:42][CH2:43]OC1C=C(N)C=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:43][CH2:42][CH2:41][N:40]([CH2:39][C:38]2[CH:66]=[CH:67][CH:68]=[C:69]([C:70]([F:71])([F:72])[F:73])[C:37]=2[Cl:36])[CH2:52][CH:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Reactant: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
(3-Hydroxy-benzyl)-carbamic acid tert butyl ester was dissolved in THF, triphenylphosphine (0.44 g, 2.2 mmole), 3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine (1.0 g, 2.3 mmole) and DIAD (0.43 ml, 2.2 mmole) were added subsequently. The mixture was stirred overnight at room temperature. The reaction was concentrated, chromatographed on silica gel (0 to 15% EtOAc/hexanes) to give the titled compound (0.51 g, 48%). MH+652.0
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[CH2:9]([N:11]([CH2:14][CH2:15]Cl)[CH2:12][CH3:13])[CH3:10].[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:10][CH2:9][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCSc1nnc(N)s1
Yield: 81.9 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (13.3 g), diethylaminoethylchloridehydrochloride (17.2 g), and potassium hydroxide (11.2 g) were stirred in methanol (200 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 19.0 g of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][CH:10]=O)[CH:5]=[CH:6][CH:7]=1.CN(C)C(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:60](Br)([F:62])[F:61]>C1COCC1.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][CH:10]=[C:60]([F:62])[F:61])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(Br)Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)c4cccc(Br)c4)c3)ncnc21
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=C(F)F)c4cccc(Br)c4)c3)ncnc21
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a solution of 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (0.05 g, 0.00009 mol) in N,N-dimethylacetamide (2 mL, 0.02 mol) was added triphenylphosphine (0.1 g, 0.0006 mol), dibromodifluoromethane (50 uL, 0.0006 mol) and 0.76 M zinc in THF (0.7 mL). The reaction was stirred at room temperature for 18 hs. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAc, Hexane (1:2) to give 4-{1-[1-(3-bromophenyl)-4,4-difluorobut-3-en-1-yl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (20 mg, 40%) as a clear oil. m/z=560, 562 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[NH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A solution of (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To this mixture was added benzyl chloroformate (0.77 mL, 5.5 mmol), followed by triethylamine (1.39 mL, 10 mmol). After removing the ice bath, the reaction was stirred for 4 h. The mixture was poured into ice water and extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using EtOAc in hexanes (0-40%) gave benzyl((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g, 77%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 5H), 5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H), 2.10-1.79 (m, 2H), 1.45 (s, 9H).