Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:14])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1C=O

Procedure:
4.5 g (30 mmol) of 2-carboxybenzaldehyde, 17.1 (120 mmol) of iodomethane and 12.4 g (90 mmol) of potassium carbonate were stirred in 85 ml of acetone for 24 hours. The solvent was removed by evaporation and the residue was partioned between 50 ml of water and 50 ml of ether. The aqueous layer was washed with 3×50 ml portions of ether. The combined organic extracts were washed with 30 ml each of 1M sodium thiosufate and saturated sodium cloride solutions and dried over MgSO4. The solvent was removed by evaporation. The residue was subjected to flash chromatography (silica gel, 10% ethyl acetate/hexanes) to give the title compound as a clear colorles oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:33]2[CH2:34][CH2:35][CH:30]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=[CH:27][C:26]=3[CH3:29])[CH2:31][CH2:32]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Oc3ccc(F)c(F)c3)cc2)CC1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3,4-Difluorophenoxy)benzaldehyde (41.0 mg, 0.170 mmol) and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (45.0 mg, 0.170 mmol) in 1,2-dichloroethane (5.00 mL) was added sodium triacetoxyborohydride (110 mg, 0.520 mmol) and AcOH (10.0 μL, 0.170 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was quenched by saturated NaHCO3 solution (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo. The crude product was purified by preparative TLC using 5% NH3 {2.0 M in MeOH) in CH2Cl2 to give the desired product N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (44.0 mg, 54.0%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].O>O1CCCC1.CCCCCC>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][C:10]2[S:11][C:12]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of Example 1B (2.4 g, 0.01 mol) in dry tetrahydrofuran was added n-butyl lithium 4.4 mL, 2.5 M in hexane) at −78° C. drop wise. After stirring at this temperature, tributyltin chloride (3.0 mL, 0.011 mol) was added slowly. The solution was then stirred for 3 hours while warming up to room temperature. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with sat. NH4Cl, brine, and then dried over magnesium sulfate. The solution was filtered, concentrated, and purified to give 4.85 g of the title compound as a clear oil (93% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.77-1.74 (m, 33H) 4.40-4.63 (m, 1H) 6.84-6.95 (m, 2H) 7.12 (s, 1H) 7.14 (m, 2H). MS (ESI) m/z 526.2 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.Cl.C[O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1)=[C:13]([C:34]1[C:35]([C:39]#[N:40])=[CH:36][S:37][CH:38]=1)[CH:12]=[CH:11]2>ClCCl>[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:24]=1)=[C:13]([C:34]1[C:35]([C:39]#[N:40])=[CH:36][S:37][CH:38]=1)[CH:12]=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cscc3C#N)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: N#Cc1cscc1-c1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Slowly add boron tribromide in dichloromethane (4 M, 182 μL, 728.0 μmol) to a solution of 4-(6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl)thiophene-3-carbonitrile hydrochloride (95 mg, 182.3 μmol) and dichloromethane (4 mL) stirring at 0° C. Stir the mixture at 0° C. for 1.5 hours. Quench the mixture with aqueous sodium bicarbonate. Extract the mixture 3 times with 20% methanol/dichloromethane. Wash the combined organic layers with water. Dry the resulting solution over sodium sulfate, filter, and concentrate to dryness. Purify the residue by flash chromatography on silica to obtain the title compound (52 mg, 111.2 μmol).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4].CI.[CH3:38]COC(C)=O>CN(C=O)C>[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[N:22]([CH3:38])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Sodium hydride (14 mg, 0.34 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester from Example E45 (125 mg, 0.28 mmol) in DMF (2 ml) at 0° C. The mixture was stirred for 20 min at room temperature then cooled down to 0° C. Methyl iodide (0.09 ml, 1.4 mmol) was added and the mixture was stirred for 20 h at room temperature. EtOAc was added and the mixture was washed with 0.3M KHSO4 then brine, dried, concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (46 mg, 36%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].II.[O:12]1[CH2:15][CH2:14][CH2:13]1.[NH4+].[Cl-]>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:15][CH2:14][CH2:13][OH:12])=[CH:3][CH:4]=1
Reactant: C1COC1
Reactant: Fc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OCCCc1ccc(F)cc1
Yield: 51.6 %

Procedure:
A Grignard reagent was prepared from 4-bromo-1-fluorobenzene (8.0 g), magnesium turnings (1.10 g), and iodine (one small crystal) in THF (40 ml). Oxetane (2.3 g) in THF (10 ml) was added at RT and the reaction mixture was heated at reflux overnight. The cooled solution was poured into aqueous saturated NH4Cl (100 ml), extracted with ER (2×150 ml) and the combined, dried (Na2SO4) extracts were evaporated. The residual oil was purified by flash chromatography over silica gel (Merck 9285, 5.0 cm wide column), eluting with ER-CX (1:5→1:3). The resultant oil was further purified by distillation to give the title compound (3.15 g) as a colourless oil, b.p. 150°/0.8 torr.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1>C(OCC)C>[CH3:5][O:4][P:1]([C:16]([OH:17])=[CH:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:2])[O:6][CH3:7]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: COP(OC)OC
Solvent: CCOCC
Product: COP(=O)(OC)C(O)=Cc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
At 0° C., a solution of 6.9 g of trimethyl phosphite in 20 ml of diethyl ether is added dropwise under agitation to a solution of 9.5 g of 4-chlorophenylacetic acid chloride in 50 ml of diethyl ether. The mixture is agitated for another 90 minutes, the thus-obtained precipitate is vacuum-filtered, yielding 9.3 g (71%) of 2-(4-chlorophenyl)-1-hydroxyethenephosphonic acid dimethyl ester, mp 89°-92° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:2]=1.O1C[CH2:22][CH2:21][CH2:20]1.[H-].[Na+].C(Br)C=C>O>[CH2:22]([O:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH:21]=[CH2:20]
Reactant: OC(c1cccnc1)c1cccc2ccccc12
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOC(c1cccnc1)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet is added 2.35 gm of the 3-pyridyl-1-naphthylcarbinol and 100 ml of anhydrous tetrahydrofuran. The system is cooled to 0° C. and after cooling 0.26 gm sodium hydride is added. The system is stirred for an additional 20 minutes and 1.1 ml of allyl bromide is added. The system is allowed to come to room temperature over 1/2-hour and is stirred there for an additional 2 hours. Afterwards, the system is heated at reflux for 17 hours. At this time, water is added to the system and the product extracted with methylene chloride. The methylene chloride is then washed with water and dried over sodium sulfate. The methylene chloride is removed by stripping to give the 3-pyridyl-1-naphthylcarbinol allylether.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=3[Br:22])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.BrC1C=CC=CC=1CBr>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Br:22])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Agent: BrCc1ccccc1Br
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2Br)c1=O

Procedure:
The title compound was prepared from compound 1 used the procedures described in the synthesis of compound 10, except that 2-bromo benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.45 (d, J=7.8 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 5.28 (s, 1H), 4.93-5.05 (ABq, 2H, J=36.4, 16.4 Hz), 3.22 (m, 1H), 3.19 (m, 3H), 3.09 (m, 1H), 2.84 (d, J=12.6 Hz, 1H), 2.63 (t, J=10.5 Hz, 1H), 2.42 (t, J=10.9 Hz, 1H), 1.97 (d, J=11.1 Hz, 1H), 1.58-1.69 (m, 1H), 1.38-1.48 (m, 2H). MS (ES) [m+H] calc'd for C17H22BrN4O2, 393.1. found, 393.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].[NH3:13]>>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[C:4]=1[NH2:13]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Product: Nc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C
Yield: 35.6 %

Procedure:
A solution of 1,2,3-trifluoro-4-nitrobenzene (1) (1.00 g, 5.64 mmol, 1.00 equiv) in methanolic ammonia (1.5 mL) was taken in microwave vial and heated to 70° C. for 90 min in the microwave. The solvent was evaporated under vacuum to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:49) to furnish compound 2 (0.350 g, 35.6%) as yellow solid. TLC: 10% EtOAc/Hexane (Rf: 0.10); 1H NMR (500 MHz, DMSO-d6): δ 7.94-7.91 (m, 1H), 7.51 (s, 2H), 6.75-6.70 (m, 1H); LC-MS: m/z=173 (M+-1) at RT 3.15 (99.8% purity)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.CC(C)=O>[CH2:16]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2Cc1ccccc1
Temperature: 25 °C

Procedure:
3,6-Dibromocarbazole 2 (112.0 g, 0.344 mol), benzyl bromide (41 ml, 0.344 mol), and nBu4NHSO4 were mixed in 200 ml of acetone and stirred at room temperature under nitrogen until dissolved. KOH (19.3 g, 0.344 mol) was then added to the above transparent solution and the resultant mixture was refluxed for 4 hours, where a white precipitate was observed. The hot mixture was concentrated to remove the majority of acetone. Upon cooling, additional white precipitate appeared. The precipitate was filtered, dissolved in methyl-t-butyl ether, washed with water, dried over Na2SO4, and concentrated to yield a major amount of pure N-benzyl-3,6-dibromocarbazole 3. The filtrate was also washed with water and extracted with methyl-t-butyl ether, dried over Na2SO4, concentrated, and purified over 120 g SiO2 with hexane and hexane:ethylacetate (95:5) eluents to yield a minor amount of pure N-benzyl-3,6-dibromocarbazole 3. The combined yield from crystallization and chromatography was 49 g (35%) of N-benzyl-3,6-dibromocarbazole 3.
Reaction SMILES: C([C:6]1[O:7][C:8]2[CH:16]=[C:15](O)[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)(OCC)=O.ClCC1C=C(C=CC=1)OCC1C=CC2C(=CC=CC=2)N=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O>[O:12]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH:6]=[CH:11]1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=c1ccoc2ccccc12

Procedure:
A mixture of l.5 g (6.41 mmoles) of 2-carboethoxy-7-hydroxy4-oxo-4H-l-benzopyran, l.82 g (6.41 mmoles) of 2-(3-chloromethylphenoxy)methylquinoline and 0.886 g of potassium carbonate in 12 ml of dimethylformamide and 96 ml of acetone is refluxed for 2 days, cooled, concentrated in vacuo and the residue taken up in water and is extracted into ethyl acetate. The solution is concentrated and the crude product is recrystallized from ethyl acetate to give 0.585 g of 2-carboethoxy-7-(3-quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a pale yellow solid having an m.p. of 123°-24° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:31]1([OH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Clc1cc2c(cn1)c(Oc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (160 mg, 0.307 mmol), phenol (43.3 mg, 0.460 mmol), copper(i) iodide (5.84 mg, 0.031 mmol), cesium carbonate (200 mg, 0.613 mmol) and N,N-dimethylglycine (9.49 mg, 0.092 mmol) were taken up in 1,4-Dioxane (2.0 ml) in a 25 mL microwave vial. The vial was evacuated and back-filled with N2 (3×) and the reaction mixture was allowed to stir at 100° C. for 6 h. NH4OH was added into the reaction mixture and extracted with EtOAc (2×). The combined organic extracts were washed with water, brine and dried over Na2SO4. After concentration the crude product was purified on silical gel 0-50% EtOAc/Hexanes and yielded 6-chloro-3-phenoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (120 mg, 0.246 mmol, 80% yield). MS: [M+H]+ m/z 488.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:30])C(=O)C1>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[C:21]=1[I:30])[CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1cn2cccnc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)OCc1ccccc1)c1nc2ncccn2c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-imidazo[1,2-a]pyrimidin-2-yl-ethyl)-carbamic acid benzyl ester (5.3 g, 17.90 mmol) in acetonitrile (30 mL) was added n-iodosuccinimide (4.0 g, 17.90 mmol) and stirred at rt overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide [1-(3-iodo-imidazo[1,2-a]pyrimidin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 422.8 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1(CCO)OCCC[O:5]1)[CH2:2][CH3:3].C(OCC)(=O)CC(C)=O.[CH3:22][C:23]([CH3:28])([CH2:26][OH:27])[CH2:24][OH:25]>>[CH3:3][C:2]1([CH2:1][CH2:4][OH:5])[O:27][CH2:26][C:23]([CH3:28])([CH3:22])[CH2:24][O:25]1
Reactant: CC(C)(CO)CO
Reactant: CCCC1(CCO)OCCCO1
Solvent: CCOC(=O)CC(C)=O
Product: CC1(C)COC(C)(CCO)OC1
Yield: 55 %

Procedure:
The same procedure as in the steps (8a) and (8b) of Example 8 was repeated using ethyl acetoacetate, and 2,2-dimethyl-1,3-propanediol to obtain the title compound (7.3 g, total yield: 55%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14]>CCO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(N)(=O)=O)cc1S(N)(=O)=O
Yield: 95.3 %

Procedure:
A stirred suspension of 2-amino-4-chloro-5-sulfamoylbenzenesulfonamide (11.4 g; 40 mmol) and 10% Pd/C (750 mg) in EtOH (300 ml) was hydrogenated at 1 bar until hydrogen consumption ceased (24 h). The reaction mixture was evaporated to dryness, resuspended in THF and filtered through celite. The filtrate was evaporated to dryness and the isolated solid washed with boiling EtOAc (2×150 ml) to give 9.58 g (95%) product.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1>CS(C)=O.C(OCC)(=O)C>[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:8][CH2:7][CH2:6][CH2:5][NH:4][CH3:3])=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1
Reactant: CNCCCO
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To sodium hydride (60% in mineral oil, 2.3 g, 57.6 mmol) in 20 mL of dimethylsulfoxide at room temperature is added a solution of 3-(methylamino)propan-1-ol (5.14 g, 57.6 mmol) in 10 mL of dimethylsulfoxide. The solution is stirred at room temperature for 1 h, and 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (5.7 g, 14.4 mmol) is added. The mixture is heated at 60° C. for 3 h, and cooled to room temperature. The reaction mixture is diluted with ethyl acetate, and washed with water and saturated sodium chloride. The organic layer is dried over magnesium sulfate, and concentrated to a residue. The residue is triturated with small amount of acetone, then hexanes, and chromatographed over silica gel, eluting with a gradient of 100% ethyl acetate to 100% methyl alcohol. Concentration provides 5-chloro-6-{2,6-difluoro-4-[3-(methylamino) propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a white solid (2.7 g). MS: m/z 465.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([CH2:35][C:36](=O)[CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]([CH3:37])[CH2:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(=O)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzylacetone.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].N1C=CC=CC=1.[Cl:19][C:20](OCC)=O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[O:7][N:6]=[C:4]([C:3]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:2]=2[CH3:1])[N:5]=1
Reactant: Cc1ccc(C(N)=NO)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2noc(Cl)n2)c(C)c1

Procedure:
Under an inert atmosphere, 10.5 g of 2,4-dimethyl benzamidoxime are dissolved in 40 ml of anhydrous toluene; 6.5 ml of pyridine and 7.6 g of ethyl chloroformate are added.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]([Cl:10])(Cl)=[O:8].[ClH:11]>[Cl-].C[N+](C)(C)CC1C=CC=CC=1>[Cl:11][CH2:3][CH2:2][CH2:1][C:7]([Cl:10])=[O:8].[C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: O=C(Cl)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O=C1CCCO1
Product: O=C(Cl)CCCCl
Temperature: 130 °C

Procedure:
430 parts of 4-butyrolactone and 47 parts of trimethylbenzylammonium chloride are initially taken in a 1 l stirred reactor which is equipped with a thermometer, inlet tubes for phosgene and hydrogen chloride and 2 low-temperature coolers set at -20° C. and -70° C. respectively. The mixture is heated to 130° C. 560 parts of phosgene and 120 parts of hydrogen chloride are passed in over 5.5 hours. Thereafter, nitrogen is passed in until the reaction mixture no longer contains any phosgene. Working up by distillation gives 620 g of 4-chlorobutyryl chloride and 30.5 g of butyrolactone. The distillation residue of 75 g, which consists of the catalyst and chlorobutyroyloxybutyryl chloride, can be reused for further batches. The yield of 4-chlorobutyryl chloride is 88 mol %, based on butyrolactone used.