Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:17]1([N:23]2[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:27]4[N:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:24]=[N:25][N:26]=4)[CH2:29][CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Reactant: O=C(O)C(=O)c1c[nH]c2c(Br)ncc(F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.0 g, 17.5 mmol) was dissolved in DMF (100 mL) and treated with 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.0 g, 17.5 mmol), Hunig's base (9.2 mL, 52.6 mmol) and TBTU (5.6 g, 17.5 mmol) and the reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A white solid precipitated out and it was collected by filtration and recrystallized twice with MeOH to afford the title compound (4.58 g) as a white solid. The mother liquid was concentrated and purified using silica gel (CH2Cl2 to 5% MeOH/CH2Cl2) to afford more title compound (1.8 g). 1HNMR (500 MHz, DMSO) δ 8.47 (s, 1H), 8.16 (s, 1H), 7.70-7.59 (m, 5H), 3.67 (m, 2H), 3.44 (m, 2H), 3.37 (m, 2H), 3.20 (m, 2H). LCMS: m/e 499 (M+H)+, ret time 1.50 min (method 1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(OC(=O)C)(=O)C>[Br:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Br:1])[CH:9]=1)[O:11][C:21](=[O:22])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[CH:5]2
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: O=Cc1cc(Br)cc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc3cc(Br)cc(Br)c3oc2=O)cc1
Temperature: 80 °C

Procedure:
3,5-Dibromo-2-hydroxybenzaldehyde (30.0 g, 107 mmol) [CAS-Nr. 90-59-5] and 4-methoxyphenylacetic acid (35.7 g, 166 mmol) are heated in 51 ml acetic anhydride and 60 ml triethylamine overnight at reflux. The reaction mixture is cooled down to 80° C. and poured onto 1000 ml 2 M sodium hydroxide under stirring. After 5 min the precipitated product is filtered by vacuum, washed with water and digested two times with 100 ml ethanol. 6,8-Dibromo-3-(4-methoxy-phenyl)-chromen-2-one is obtained as a yellow solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[N+](=[CH2:27])=[N-].B(F)(F)F.CCOCC>ClCCl>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:27])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-β-D-mannopyranose (2.94 g) in dichloromethane (30 ml) at 0° C. is reacted with excess diazomethane in dichloromethane containing boron trifluoride etherate (0.12 ml). After 2 hours, the reaction mixture is filtered and excess diazomethane is destroyed with glacial acetic acid. The filtrate is washed successively with aqueous sodium hydrogencarbonate and water, dried, and evaporated in vacuo to a syrup (3.0 g). A portion of the product is crystallized from ethanol, m.p. 102°-103°, [α]D27 -16.0±1.0° (C 1.02, chloroform).
Reaction SMILES: C=O.[BH3-][C:4]#N.[Na+].[C:7]1([CH:13]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:14][NH:15][CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)=O.CO>[C:35]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][N:15]([CH3:4])[CH:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][N:27]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: [BH3-]C#N
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCC(c2ccccc2)c2ccccc2)nc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(c1ccccc1)c1ccccc1)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
Add paraformaldehyde (57 mg) and NaBH3CN (46 mg, 0.734 mmol) to a solution of 6-[1-(2,2-Diphenyl-ethylamino)-indan-5-yloxy]-nicotinamide (example 9, 110 mg, 0.245 mmol) in 5% AcOH/MeOH (3 ml) and stir at ambient temperature for two days. Concentrate the reaction mixture and partition remaining residue between EtOAc and 1M aq. K2CO3. Separate layers and wash organic with 1M aq. K2CO3 and brine before dying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 74 mg of the title compound as a white solid. Mass spectrum (ion spray): m/z=464 (M+1); 1HNMR (CDCl3): 8.54 (s, 1H), 8.15 (d, 1H), 7.30-7.15 (m, 10H), 6.95-6.81 (m, 4H), 5.81 (br. s, 2H), 4.39 (t, 1H), 4.20 (t, 1H), 3.02 (d, 2H), 2.94-2.75 (m, 2H), 2.27 (s, 3H), 2.06 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36](O)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1([N:45]=[C:46]=[N:47]C2CCCCC2)CCCCC1.ON1C(=O)CCC1=O.N#CN.[Na]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([NH:47][C:46]#[N:45])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)NC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A mixture of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (0.030 g, 0.052 mmol; Example 141), N,N′-dicyclohexylcarbodiimide (10.64 mg, 0.052 mmol) and N-hydroxysuccinimide (5.94 mg, 0.052 mmol) in 3 mL of THF was stirred while cooling with an ice bath for 3 h. The reaction mixture was filtered and the filtrate was added dropwise to a solution of monosodium cyanamide (10.90 mg, 0.170 mmol) in 2 mL of water at an ice bath temperature. The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was purified by reverse phase HPLC (40 to 90% water/acetonitrile gradient with 0.1% TFA). Desired fractions were then collected and concentrated to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(#N)C.ClCCl>[CH2:16]([N:18]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: COc1ccc(OCCCl)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: CC#N
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
4-(2-chloroethoxy)-1-methoxy-2-nitrobenzene (0.15 g, 0.67 mmol) was dissolved in acetonitrile (1 ml). Excess diethylamine (1.5 ml, 17.7 mmol) was added and the reaction heated in the microwave (T=120° C., 40 min) to complete conversion. The reaction mixture was diluted with dichloromethane, then washed with 5M sodium hydroxide and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as an orange oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].F[SiH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=3)=[CH:17][CH:18]=2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: CCCBr
Reactant: Fc1cc(-c2ccc(C3CC[SiH](F)CC3)cc2)cc(F)c1F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](c2ccc(-c3cc(F)c(F)c(F)c3)cc2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.5 g (20 mmol) of 4'-(4-fluoro-4-silacyclohexyl)-3,4,5-trifluorobiphenyl to obtain 4'-(trans-4-n-propyl-4-silacyclohexyl)-3,4,5-trifluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 5.9 g of the trans isomer (yield 91%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:15]([O-:17])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]=[C:53]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>ClCCl>[CH3:67][C:65]([CH3:68])([O:64][C:63]([NH:62][C:53]([NH:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:15](=[O:17])[CH:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:54][C:55]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:61])=[O:69])[CH3:66]
Reactant: CCOC(=O)C(OCc1ccccc1)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCCCN)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)C(OCc1ccccc1)C(=O)NCCCCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
2.6 g (10.9.10-3 mol) of ethyl 2-phenylmethoxypropanedioate are dissolved in 50 ml of dichloromethane and the mixture is cooled to 0° C. 4.34 g (22.10-3 mol) of N,N'-dicyclohexylcarbodiimide and 0.57 g (4.10-3 mol) of 1-hydroxybenzotriazole are added, the mixture is stirred for 0.5 hour, a solution of 4.21 g (10.9. 10-3 mol) of bis(1,1-dimethylethyl) [[(8-aminooctyl)imino]methylene]biscarbamate in 15 ml of dichloromethane is then added and the mixture is stirred at room temperature for 48 hours. The reaction medium is concentrated under reduced pressure and the residue is then purified by chromatography on silica using a methylcyclohexane/ethyl acetate mixture (7/3) as the eluent to give 2.7 g (yield=40.8%) of the expected product in the form of a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:22][CH3:23])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:31](I)[CH2:32][CH3:33]>O>[CH2:22]([N:3]1[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=[C:2]1[NH:1][CH2:31][CH2:32][CH3:33])[CH3:23]
Reactant: CCCI
Reactant: CCn1c(N)nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1CC
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a solution of 2-amino-3-ethyl-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (80 mg, 0.26 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-PrI (170 mg, 1.0 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at 50° C. for 3 hours, the mixture was cooled and diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1) to give 25 mg (25%) of the title compound.
Reaction SMILES: [C:1]1(C)[CH:6]=CC=C[CH:2]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.CC(C)=O>[Pt].O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:1]([CH3:6])[CH3:2])=[CH:11][CH:10]=1
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Pt]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 42.5 °C
Reaction time: 2 h

Procedure:
520 parts of toluene, 423 parts (3 mol) of 4-fluoronitrobenzene, 192 parts (3.3 mol) of acetone and 8 parts of catalyst (5% Pt on charcoal, water-moist, water content 50%) are placed in a hydrogenation autoclave. After the gas space has been flushed three times with each of nitrogen and hydrogen, the mixture is heated to from 80°=0 to 85° C. with stirring and reduced at a hydrogen pressure of from 0.2 to 1.0 MPa. When after about 2 hours the uptake of hydrogen falls sharply, the pressure is raised to 2.0 MPa and stirring is continued at 85° C for 30 minutes until there is no longer any drop in pressure. The batch is cooled to 60° C., the autoclave is let down and flushed with nitrogen, and the catalyst is filtered off on a pressure filter at from 50° to 60° C. The aqueous phase is separated off from the filtrate and toluene is distilled off until the water content of the solution is <0.02%. The solution is processed further in accordance with Example 2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16]>CN(C)C=O>[Br:1][C:13]1[CH:12]=[C:11]([C:15]#[N:16])[N:10]([CH3:9])[CH:14]=1
Reactant: Cn1cccc1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
N-Bromosuccinimide (6.2 g, 34.9 mmol) is added to a solution of 1-methyl-1H-pyrrole-2-carbonitrile (3.7 g, 34.9 mmol) in N,N-dimethylformamide (150 mL). The solution is stirred for 15 hours at ambient temperature. Another amount of N-bromosuccinimide (2.0 g, 11 mmol) is added and the mixture is stirred for 3 hours. The product is purified by chromatography over silica gel (ethyl acetate/heptane gradient) to obtain the expected product in the form of a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=C(NC2N=CN=C(NC(C3CC3)=O)C=2)C(=O)[N:4]2C(C3C=CC=C(F)C=3)(C)NC(=O)[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Cl.[Br:41][C:42]1[C:47](=[O:48])[N:46]2[C:49]3([NH:55][C:56](=[O:57])[C:45]2=[C:44]([Cl:58])[CH:43]=1)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3>C(#N)C>[Br:41][C:42]1[C:47](=[O:48])[N:46]2[C:49]3([NH:55][C:56](=[O:57])[C:45]2=[C:44]([Cl:58])[CH:43]=1)[CH2:54][CH2:53][N:52]([CH2:7][CH2:2][C:3]#[N:4])[CH2:51][CH2:50]3
Reactant: O=C1NC2(CCNCC2)n2c1c(Cl)cc(Br)c2=O
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1CCC2(CC1)NC(=O)c1c(Cl)cc(Br)c(=O)n12
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A flask was charges with 6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione hydrochloride (1, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was added. The reaction mass was cooled to 0° C. and potassium carbonate (281 mg, 2.03 mmol) was added followed by addition of 2-bromoacetonitrile (2, 218 mg, 1.63 mmol). The reaction mass was stirred at room temperature for 10 h. After completion, the solvent was removed under reduced pressure to get the crude. The crude was purified by Biotage snap using 1-3% methanol in dichloromethane. The desired fractions were concentrated to get 3-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-yl)propanenitrile (3) as brown solid. Yield: 0.42 g, 83%; MS (ESI) m/z 373.18 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.25 (s, 1H), 3.75 (s, 2H), 3.15-3.10 (m, 2H), 2.87-2.72 (m, 2H), 2.66-2.60 (m, 2H) 1.57-1.54 (m, 2H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.CCCCCCC.[CH2:21]([C:23]1[CH:28]=CC=C[CH:24]=1)C.[CH3:29][O:30][C:31](=[O:55])[CH2:32][C:33]1[CH:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:36]=[C:35]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:34]=1.BrCC(C)=C>C1COCC1>[CH3:29][O:30][C:31](=[O:55])[CH:32]([C:33]1[CH:34]=[C:35]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:36]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=1)[CH2:24][C:23]([CH3:28])=[CH2:21]
Reactant: CCc1ccccc1
Reactant: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: C=C(C)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A 2M solution of LDA in THF-heptane-ethylbenzene (21.5 mL, 43.0 mmol) was added dropwise over 12 min to a stirred solution of (3,5-bis-benzyloxyphenyl)acetic acid methyl ester (13.0 g, 35.9 mmol) in THF (80 mL) at −78° C. under a nitrogen atmosphere. The temperature was maintained below −70° C. for a further 50 min then 3-bromo-2-methylpropene (4.0 mL, 39.7 mmol) was added in one portion and the reaction mixture was warmed to 0° C. After 2 h the mixture was concentrated in vacuo, diluted with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica, 0-10% EtOAc in petroleum ether) to afford the title product as a yellow oil (14.1 g, 94%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCCCc1nc(-c2ccccc2)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCc1nc(-c2ccccc2)cs1
Temperature: 100 °C
Yield: 91 %

Procedure:
Sodium azide (263 mg, 4.05 mmol) was added to a solution of 3-(4-phenylthiazol-2-yl)propyl methanesulfonate (0.4 g, 1.35 mmol) in dry DMF (8 mL), and the reaction mixture was heated to 100° C. for 2 h. The mixture was allowed to cool down to room temperature and diluted with EtOAc. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(3-azidopropyl)-4-phenylthiazole (0.3 g, yield 91%) as a pale orange liquid, which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.91-7.89 (m, 2H), 7.46-7.41 (m, 2H), 7.36-7.31 (m, 2H), 3.49-3.44 (t, J=6.7 Hz, 2H), 3.20-3.15 (t, J=7.5 Hz, 2H), 2.21-2.12 (m, 2H). MS (ESI) m/z: Calculated for C12H12N4S: 244.08. found: 245.2 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][NH:28][C:24]=2[CH:23]=[CH:22][N:21]=1>ClCCl>[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][N:28]([CH:18]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: C1=COCCC1
Reactant: Clc1nccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1nccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
p-Toluenesulfonic acid monohydrate (2.4 g, 13 mmol) and 3,4-dihydro-2H-pyran (99%, 45 mL, 520 mmol) were sequentially added to a suspension of 4-chloro-1H-pyrazolo[4,3-c]pyridine (20.0 g, 130 mmol) in dichloromethane (400 mL). The reaction mixture was allowed to stir at room temperature for 24 hours, at which time it was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: 10%, then 30%, then 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 27.51 g, 115.7 mmol, 89%. LCMS m/z 238.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=6.0 Hz, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.47 (dd, J=6.0, 0.9 Hz, 1H), 5.73 (br dd, J=9.0, 2.7 Hz, 1H), 3.97-4.04 (m, 1H), 3.72-3.80 (m, 1H), 2.43-2.53 (m, 1H), 2.07-2.20 (m, 2H), 1.65-1.85 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][P:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].Br[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([P:5]([O:7][CH2:8][C:9]([F:12])([F:10])[F:11])([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[O:6])[CH2:21][C:22]([CH3:45])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])=[C:32]2[C:28](=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44])[CH2:29][O:30][C:31]2=[O:41]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CBr)C(=O)OC2
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added a solution of 1N NaN (TMS)2 in THF (0.88 mL, 0.88 mmol). The solution was stirred at room temperature for 30 minutes, whereupon a solution of 6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture was stirred overnight when a precipitate was observed. The reaction mixture was worked up by addition of a saturated aqueous solution of ammonium chloride and extraction of the product with EtOAc. The organic extract was dried and the product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg (48%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H, J=4, 12, 23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; MS (m/z) 701.2 [M+Na]+.