Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([F:43])([F:42])[F:31])[CH:7]=[CH:6][CH:5]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(-c5ccccc5C(F)(F)F)c4)n3n2)cc(OC)c1OC
Temperature: 150 °C
Yield: 27.1 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (50 mg, 0.106 mmol), 2-trifluoromethylphenyl boronic acid (30.3 mg, 0.159 mmol), potassium carbonate (44.1 mg, 0.318 mmol), and Combiphos catalyst POPd1 ((dihydrogen di-κ-chlorotetrakis(di-tert-butylphosphinito-κP)dipalladate(2-)) (5.0 mg, 0.005 mmol) was added 1,4-dioxane (1.8 mL) and distilled water (0.2 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 150° C. for a total time of 1 hour. After cooling to room temperature, poured reaction mixture into dichloromethane (50 mL) and washed with distilled water (3×25 mL) and brine (1×25 mL). Dried over MgSO4, filtered and removed solent under reduced pressure to give a gold oil. Dissolved oil in dichloromethane and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (20:80 to 70:30) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-[2′-(trifluoromethyl)-1,1′-biphenyl-3-yl]-N-(3,4,5-trimethoxyphenyl) imidazo[5,1-f][1,2,4]triazin-2-amine (0.0154 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.59 (d, J=7.90 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.71 (dd, J=7.9, 7.1 Hz, 1H), 7.62 (dd, J=7.3, 7.5 Hz, 1H), 7.54 (dd, J=7.7, 7.9 Hz, 1H), 7.45 (d, J=6.6 Hz, 1H), 7.39 (d, J=7.1 Hz, 1H), 7.05 (s, 2H), 3.67 (s, 6H), 3.61 (s, 3H), 2.51 (s, 3H). MS m/z 536 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:18]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(F)cc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 55.1 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 210 mg, 1.02 mmol) and 4-fluoro-2-trifluoromethyl-benzyl bromide (470 μL, 3.04 mmol) in N,N-dimethylformamide (10 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40M system, eluting with 0-0.5% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-fluoro-2-trifluoromethyl-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (215 mg, 55%) as an off-white solid. APCI-MS (M+H) 383.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CON(C)[C:18]([CH:20]1[CH2:22][CH:21]1[CH3:23])=[O:19]>CCCCCC>[CH3:9][C:4]1[CH:3]=[C:2]([C:18]([CH:20]2[CH2:22][CH:21]2[CH3:23])=[O:19])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CON(C)C(=O)C1CC1C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C)cc(C(=O)C2CC2C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-meta-xylene (5.7 mL in 120 mL of dry tetrahydrofuran) at -78° C. was added 30.6 mL of a 1.4M solution of n-butyllithium in hexane and the mixture stirred at low temperature. After 15 minutes, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-N-methyl-amide (5.0 g in 50 mL tetrahydrofuran) was added dropwise over 5 minutes and the mixture then allowed to warm slowly to room temperature. After 1 hour, the reaction was quenched by the addition of 20 mL 2N hydrochloric acid and 40 mL water. This was extracted with ethyl acetate washed with saturated sodium bicarbonate and brine then dried over sodium sulfate to give 6.95 g of the crude title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>ClC(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: CNCCO
Reactant: O=C(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(CCO)C(=O)N1CCCC1
Reaction time: 6 h
Yield: 40.1 %

Procedure:
To a stirred solution of 7.5 parts of 2-(methylamino)ethanol in 75 parts of trichloromethane were added 9.8 parts of N,N-diethylethanamine while cooling in an ice bath. A solution of 13.4 parts of 1-pyrrolidinecarbonyl chloride in 52.5 parts of trichloromethane was added dropwise (exothermic reaction, the temperature rose from -10° C. to ~0° C.). Upon complete addition, stirring was continued for 6 hours at room temperature. Another portion of 1.5 parts of 2-(methylamino)ethanol was added and stirring was continued over weekend at room temperature. The separated organic layer was washed with a hydrochloric acid solution 5% and water, dried, filtered and evaporated, yielding 7 parts (40.1%) of N-(2-hydroxyethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int. 30).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])[CH3:17].C(O)(C)C>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Yield: 83 %

Procedure:
The compound was prepared according to general procedure E with 4-hydroxybenzaldehyde (3.3 mmol) in dry acetone (15 ml), anhydrous K2CO3 (4.3 mmol), and ethyl-2 bromopropionate (3.6 mmol) at reflux for 2 h45. Isopropanol was added and evaporated by azeotropic distillation with ethyl-2-bromopropionate. 609 mg of pure compound were obtained (83% yield). 1H NMR (250 MHz, CDCl3): δ 1.10 (t, J=7.1 Hz, 3H), 1.52 (d, J=6.8 Hz, 3H), 4.10 (q, J=7.1 Hz, 2H), 4.76 (q, J=6.8 Hz, 1H) 6.85 (d, J=8.7 Hz 2H), 7.70 (d, J=8.9 Hz, 2H), 9.74 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 14.0, 18.2, 61.4, 72.4, 115.1, 130.4, 131.8, 162.4, 171.1, 190.5
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[O:11]=[C:12]1[C:25]2[CH:24]=[CH:23][C:22]([C:26](O)=[O:27])=[CH:21][C:20]=2[S:19](=[O:30])(=[O:29])[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:11]=[C:12]1[C:25]2[CH:24]=[CH:23][C:22]([C:26]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:27])=[CH:21][C:20]=2[S:19](=[O:30])(=[O:29])[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2S(=O)(=O)c2cc(C(=O)N3CCc4occc4C3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.346 g (1.2 mmol) of 9-oxo-9H-thioxanthene-3-carboxylic acid 10,10-dioxide and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[S:16])[N:6]([CH2:9][CH:10]2CCCC[CH2:11]2)[C:7]=1[NH2:8].[CH:18](OCC)(OCC)[O:19]CC.[CH2:28](O)C>>[CH3:18][O:19][CH2:11][CH2:10][CH2:9][N:6]1[C:7]2[N:8]=[CH:28][NH:1][C:2]=2[C:3](=[O:17])[NH:4][C:5]1=[S:16]
Reactant: CCO
Reactant: Nc1c(N)n(CC2CCCCC2)c(=S)[nH]c1=O
Reactant: CCOC(OCC)OCC
Product: COCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Yield: 9 %

Procedure:
5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.6 g, 12.2 mmol) was dissolved in ethanol (10 mL) and triethyl orthoformate (10 mL) and the reaction mixture was refluxed for 2.5 h. The solvents were evaporated off and the resulting brown solid was purified by flash chromatography (heptane/ethyl acetate, 4:1-1:1) to give the title compound (110 mg, 9%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][CH3:13])[C:8](=[O:14])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[CH:30]=[C:25]3[CH:24]=[CH:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([N:9]1[CH2:10][C:11]2[C:2]([O:37][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[CH:30]=[C:25]5[CH:24]=[CH:23][N:22]([C:19]6[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=6)[C:26]5=[N:27][CH:28]=4)=[CH:36][CH:35]=3)=[CH:3][CH:4]=[N:5][C:6]=2[NH:7][C:8]1=[O:14])[CH3:13]
Reactant: CCN1Cc2c(Cl)ccnc2NC1=O
Reactant: Oc1ccc(-c2cnc3c(ccn3-c3ccc(F)cc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1Cc2c(Oc3ccc(-c4cnc5c(ccn5-c5ccc(F)cc5)c4)cc3)ccnc2NC1=O
Reaction time: 2 h

Procedure:
Into a 10-mL microwave vial equipped with a stir-bar was added 5-chloro-3-ethyl-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (30.00 mg; 0.14 mmol), 4-[1-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenol (64.70 mg; 0.21 mmol) and cesium carbonate (138.55 mg; 0.43 mmol). The mixture was suspended in DMF (2.00 ml). The vial was then loaded onto the microwave reactor and run at 160° C. for 2 h. The reaction mixture was filtered through a bed of silica under reduced pressure. The crude material was purified via Biotage eluting with a gradient of 50 to 100% EtOAc in Hexanes to provide 275 as an off-white solid. LC-MS (M+H=480, obsd.=480). 1H-NMR: (DMSO-D6) δ 9.66 (s, 1H); 8.64 (d, 1H); 8.37 (d, 1H); 7.97 (m, 4H); 7.84 (d, 2H); 7.41 (t, 2H); 7.30 (d, 2H), 6.78 (d, 1H); 6.27 (d, 1H); 4.54 (s, 2H); 3.40 (q, 2H); 1.11 (t, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[C:15]3[CH2:16][CH2:17][N:7]([C:8]=23)[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]1=2)[C:2]#[CH:3].[CH2:22]=[O:23].[CH3:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>O1CCOCC1.ClCCl.CCOCC.[Cu]Cl>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:17][C:16]#[C:15][CH2:8][N:7]2[C:22](=[O:23])[C:2]3[CH:3]=[CH:14][CH:13]=[C:12]4[CH2:9][CH2:10][N:4]([C:1]=34)[C:5]3[CH:21]=[CH:20][CH:19]=[CH:18][C:6]2=3)[CH2:27][CH2:26]1.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:3]#[C:2][CH2:1][N:4]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[C:15]4[CH2:16][CH2:17][N:7]([C:8]=34)[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]2=3)[CH2:27][CH2:26]1
Reactant: CC1CCNCC1
Reactant: C#CCN1C(=O)c2cccc3c2N(CC3)c2ccccc21
Reactant: C=O
Agent: Cl[Cu]
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1CCN(CC#CCN2C(=O)c3cccc4c3N(CC4)c3ccccc32)CC1

Procedure:
A mixture of 1,2-dihydro-7-(2-propynyl)-benzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (4.45 gm, 16.2 mmole), paraformaldehyde (3.6 gm), 4-methylpiperidine (1.93 gm, 1.2 eq) and copper(I) chloride (300 mg), in dioxane (75 ml) was stirred for 16 hours at room temperature. After the reaction was complete, the mixture was diluted with dichloromethane (DCM, 300 ml). The insolubles were filtered off through a pad of celite. The solution was concentrated on a rotary evaporator to an oil (48 gm). The desired product was purified by flash chromatography over a silica gel column (100 gm, SiO2, eluted with 1% CH3OH:1% diethylamine:98% DCM, 1.5 l). The material obtained as a yellow syrup was dissolved in ether (50 ml) and filtered once. The ethereal solution was added to a solution of fumaric acid (1.9 gm, 1.0 eq) in ether (30 ml) with fast stirring. The salt crashed out as a thick gum. This mixture was diluted with ether (300 ml) and stirred for i hour, while the gum turned slowly to a solid. The solid was collected and recrystallized once from hot ethanol to afford yellow crystals: 3.9 gm, m.p. 157°-158° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 6.0 g N-t-butyloxycarbonyl-4-piperidone, 3.3 g of 2-aminophenol, 25 mL of 1,2-dichloroethane, 25 mL of glacial acetic acid, and 500 mg powdered 4 Å molecular sieves was stirred under inert atmosphere. After 30 min, 6.4 g sodium triacetoxyborohydride was added stirring was continued for 38 h. The reaction mixture was poured into 400 mL ethyl acetate and 200 mL saturated aqueous NaHCO3 and the layers separated. The organic layer was washed with brine (2×100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with a gradient of 1-3% methanol/methylene chloride containing 0.5% concentrated NH4OH gave 1-t-butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine as an orange foam.
Reaction SMILES: [Cl:1][CH2:2][Si:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.O>C1(C)C(C)=CC=CC=1>[ClH:1].[CH3:12][Si:3]([CH2:2][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1
Reactant: C[Si](C)(CCl)Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Solvent: O
Product: C[Si](C)(Cc1ccc(F)cc1)Cn1ccnc1
Product: Cl

Procedure:
After dissolving 3.25 g of chloromethyl-dimethyl-(4-fluorobenzyl)silane in 10 ml of xylene, 2.55 g of imidazole are added to the solution which is then refluxed for 12 hours. After adding 50 ml of water to the mixture and separating, the organic phase is washed with a total of 100 ml of water in 5 portions. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to solvent-free. The pale yellow oily residue is dissolved in 20 ml of ethyl acetate and gaseous hydrogen chloride is introduced to the solution until reaching a pH value of 4 to 5. The precipitated crystalline title product named is filtered in two portions at 10° C. and washed with a total of 6 ml of ethyl acetate to give the named compound in a yield of 3.41 g (80%), m.p.: 152°-154° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[BH4-].[Na+].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CO.CCOCC.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])[O:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(Br)co1
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)co1
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-furaldehyde (5.0 g, 29 mmol) in methanol (40 ml) was added sodium borohydride (1.1 g, 29 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured into water and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in N,N-dimethylformamide (30 ml) were added successively imidazole (3.9 g, 57 mmol) and t-butyldimethylchlorosilane (4.7 g, 31 mmol) with stirring, and the resulting mixture was stirred for 4 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:97) as the eluent to afford the title compound (7.4 g) in a yield of 89% as a colourless oily product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12]O)[CH2:6]1)[CH3:2].S(Br)([Br:17])=O.C(OCC)C>C1(C)C=CC=CC=1>[BrH:17].[CH2:1]([O:3][C:4](=[O:14])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][CH2:12][Br:17])[CH2:6]1)[CH3:2]
Reactant: O=S(Br)Br
Reactant: CCOC(=O)[C@@H]1CCCN(CCO)C1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Br
Product: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Yield: 131.7 %

Procedure:
A sample of the above alcohol (140 g, 0.70 mole) was dissolved in toluene (400 ml) and thionyl bromide (80 ml, 0.77 mole) was introduced with vigorous stirring. After 1.5 h the exotherm reaction had subsided and diethyl ether (400 ml) was added. The resultant precipitate was collected by filtration and washed with diethyl ether. The solid was triturated with ethyl acetate, again collected on a filter and dried to provide (R)-1-(2-bromoethyl)nipecotic acid ethyl ester hydrobromide (175 g, 73%) as a white solid, m.p. 210°-215° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>C(Cl)Cl.CO>[I:45][CH2:2][CH2:3][CH2:4][C@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCI)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl (S)-5-hydroxy-2-(t-butoxycarbonylamino)-pentanoate (5.79 g, 20.0 mmol), triphenylphosphine (8.13 g, 31.0 mmol) and imidazole (2.04 g, 30.0 mmol) in CH2Cl2 (200 mL) at room temperature is added iodine (6.35 g, 25.0 mmol), portionwise, over 30 minutes. The mixture is then stirred 16 hours at room temperature. Methanol (20 mL) is added to the solution, which is then stirred an additional 1 hour. Solvent is evaporated, and the residue is purified by chromatography (silica, 33% EtOAc/hexane) to yield t-butyl (S)-5-iodo-2-(t-butoxycarbonylamino)-pentanoate as a clear oil.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:30]>C(O)C.[Pd]>[ClH:30].[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][C:11]4[CH2:10][CH2:9][NH:8][CH2:21][CH2:20][C:19]=4[C:18]=3[CH:17]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCN(Cc2ccccc2)CC4)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCNCC4)cc1
Yield: 82.4 %

Procedure:
A mixture of 3-benzyl-9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.22 g, 0.62 mmol), 1 N hydrochloric acid (0.65 mL, 0.65 mmol) and Pd/C (10%, 0.24 g) in ethanol (50.0 mL) was reacted in a manner similar to Example 8 to give 0.168 g (80%) of a greenish solid: mp 258-260° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.08, 9.62, 7.64, 7.59, 7.31, 6.99, 3.79, 3.37-3.27, 3.22-3.12; IR (drift) 2986, 2957, 2921, 2893, 2829, 2752, 1514, 1476, 1456, 1273, 1250, 1239, 1180, 836, 800 cm−1; MS (EI) m/z 292 (M+); HRMS (FAB) calcd for C19H20N2O+H: 293.1654, found: 293.1651; Anal. Calcd for C19H20N2O.HCl: C, 69.40; H, 6.44; N, 8.52; Found: C, 68.37; H, 6.53; N, 8.27.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][CH2:12][C:13](OCC)(OCC)OCC>C(O)C>[Cl:11][CH2:12][C:13]1[S:10][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2
Reactant: COc1ccc(N)c(S)n1
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CCO
Product: COc1ccc2nc(CCl)sc2n1
Temperature: 90 °C

Procedure:
3-Amino-6-methoxy-2-pyridinethiol (0.8 g, Maybridge Co.) and 2-chloro-1,1,1-triethoxyethane (1.26 g) were combined in ethanol (5 mL) and heated at 90° C. in a sealed tube for 2 hours. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (2:1, dichloromethane:hexanes) to provide th-e title compound. 1H NMR (CDCl3, 300 MHz) δ 4.00 (3H, s), 4.88 (2H, s), 6.88 (1H, d, J=8.7 Hz), 8.10 (1H, d, J=8.7 Hz); MS (DCI/NH3) nil/z 215.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(C(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.98 min; [M+H]+=445.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[CH3:12][S-:13].[Na+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[S:13][CH3:12])[CH:5]=[O:6]
Reactant: C[S-]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CSc1c(F)cc(C=O)cc1F
Temperature: 125 °C

Procedure:
A solution of 3,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol) in DMSO (7.8 mL) was treated with a slurry of sodium methanethiolate (0.438 g, 6.25 mmol) in DMSO (0.3 mL). The solution was warmed at 125° C. for 17 min in a microwave. Upon completion, the reaction was diluted with EtOAc and washed with H2O (1×) and saturated aqueous NaCl (1×). The combined aqueous was back-extracted with EtOAc (3×), and the combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield a crude oil that was purified by silica gel column chromatography (0-30%, EtOAc-hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 7.39 (d, J 7.0 Hz, 2H), 2.58 (s, 3H).