Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[CH:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[CH2:13]([O:20][C:21](=[O:26])[CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C#CCCC(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCC#Cc1cccc(OC(F)(F)F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a degassed (Ar) solution of 1-iodo-3-trifluoromethoxy-benzene (0.54 ml, 3 mmol) in acetonitrile (30 ml) was added pent-4-ynoic acid benzyl ester (719 mg, 4 mmol; A. Rosowsky, R. A. Forsch, F. S. Queener, J. Med. Chem. 2003, 46, 1726-1736), PdCl2(Ph3P)2 (122 mg, 0.17 mmol), cuprous iodide (33 mg, 0.17 mmol) and triethylamine (1.45 ml, 10 mmol). The reaction mixture was stirred for 2.5 h at ambient temperature, poured into a solution of aqueous 10% KHSO4/ice water 1/1 and extracted two times with ether. The combined extracts were washed with aqueous 10% KHSO4 and aqueous 10% NaCl and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 1.13 g (3.2 mmol, 93%) of the title compound as yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH2:9]([N:11]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[O:18])[NH:12]1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:9]([N:11]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[O:18])[N:12]1[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1)[CH3:10]
Reactant: Fc1ccc(I)cn1
Reactant: CCN1NC(=O)CC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCN1N(c2ccc(I)cn2)C(=O)CC1(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
(200 mg, 0.90 mmol) 2-Fluoro-5-iodopyridine was dissolved in toluene (1 ml) and 1-ethyl-5,5-dimethyl-pyrazolidin-3-one [CAS 26485-97-2] (128 mg, 0.90 mmol, 1.0 equiv.) and cesium carbonate (440 mg, 1.35 mmol, 1.5 equiv.) were added under nitrogen. The mixture was stirred for 4 hours at 100° C. The crude product was purified by flash chromatography by directly loading the toluene mixture onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 50:50. The desired 1-ethyl-2-(5-iodo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (88 mg, 28% yield) was obtained as a yellow oil, MS: m/e=346.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:17](O)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Subsequently, to a solution of 1-t-butoxycarbonyl-3-hydroxyazetidine (2.5 g, 14.4 mmol) in dimethylformamide (125 ml) was added sodium hydride (55% oil dispersion) in an ice bath. After stirring the mixture for 10 minutes in the ice bath, the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methyl iodide (1.79 ml, 28 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the reaction mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, 10% aqueous acetic acid solution was added thereto in an ice bath and the reaction mixture was stirred in the ice bath for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 1-t-butoxycarbonyl-3-methoxyazetidine (2.18 g, yield 81%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[P:21](Cl)([Cl:24])([Cl:23])=[O:22]>CCOCC>[Cl:23][P:21]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([Cl:24])=[O:22]
Reactant: COC(=O)CCc1ccccc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1OP(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dry triethylamine (0.38 mL, 2.8 mmol) and methyl 3-(2-hydroxyphenyl)propanoate, 80 (0.5 g, 2.77 mmol) in dry ether (9.2 mL) were added dropwise to a solution of dry ether (5 mL) containing phosphorus oxychloride (0.25 mL, 2.8 mmol) at −78° C. under nitrogen. Following the addition, the reaction mixture was slowly allowed to warm to rt, and stirred for 1 h. The solvent was removed under reduced pressure to give crude product as an oil containing a significant amount of solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH2:13]([NH2:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:13]([NH:15][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 81447.5 %

Procedure:
A suspension of 2,4-difluoro-1-nitrobenzene (0.50 g, 0.003 mmol), ethylamine hydrochloride (0.49 g, 0.006 mmol), K2CO3 (1.66 g, 0.012 mmol) in acetonitrile (30 mL) was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated and dissolved in small amount of CHCl3. Purification by column chromatography on silica using pentane/diethyl ether 95:5 as eluent gave 0.45 g of a yellow solid. 1H NMR (CDCl3) δ 8.23-8.18 (m, 1H), 8.08 (br s, 1H), 6.49-6.45 (m, 1H), 6.38-6.32 (m, 1H), 3.34-3.27 (m, 2H), 1.38 (tr, J=7.22 Hz, 3H); 13C NMR (CDCl3) δ 167.55 (d, JCF=255.6 Hz), 147.4 (d, JCF=12.9 Hz), 129.91 (d, JCF=12.9 Hz), 128.71 (br s), 103.73 (d, JCF=24.8 Hz), 99.14 (d, JCF=27.6 Hz), 37.88, 14.05; MS (posESI) m/z=found 184.0653, calc 184.0648. Anal. (C12H18N4O2) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]2[CH2:17][S:16][C:15](=[O:18])[NH:14][NH:13]2)=[CH:6][CH:5]=1)([O-])=O>N1C=CC=CC=1.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]2[CH2:17][S:16][C:15](=[O:18])[NH:14][NH:13]2)=[CH:6][CH:5]=1
Reactant: O=C1NNC(C=Cc2ccc([N+](=O)[O-])cc2)CS1
Solvent: O
Solvent: c1ccncc1
Product: Nc1ccc(C=CC2CSC(=O)NN2)cc1

Procedure:
To a solution containing 7.5 g of 5-[2-(4-nitrophenyl)ethenyl]-5,6-dihydro-1,3,4-thiadiazin-2(3H)one (Example 46) in 300 ml of pyridine 18.0 g sodium dithionite in 150 ml of water was gradually added. The mixture was refluxed for 5 h. The organic phase was separated and evaporated to dryness in vacuo. The residue was treated with water and the product was filtered. Yield 4.0 g (60%), mp. 188°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCBr
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C

Procedure:
N-(3,4-Dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (0.30 g), bromoethane (0.12 ml) and potassium carbonate (0.56 g) was refluxed in acetone (70 ml) for 18 hours. The reaction mixture was allowed to cool to room temperature then filtered. The filtrate was concentrated in vacuo and the resulting oil separated between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (5 g). The resulting powder was subjected to chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (24.9 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[C:25]([F:27])[C:24]([OH:28])=[C:23]([F:29])[CH:22]=1)=[O:17]>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:24]3[C:23]([F:29])=[CH:22][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:26][C:25]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: COC(=O)C1CC1c1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 88 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 23 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (0.020 g, 0.08 mmol) obtained in Step C of Preparation Example 60 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.030 g, 88%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.C(O)(=O)C[C:35](CC(O)=O)([C:37](O)=[O:38])[OH:36]>C(O)CO.O>[OH:36][CH2:35][CH2:37][O:38][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)CCc2ccccc2)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-c2c(NS(=O)(=O)CCc3ccccc3)nc(-c3ccncc3)nc2OCCO)cc1
Temperature: 11 °C
Reaction time: 72 h

Procedure:
2-Phenyl-ethanesulfonic acid (6-chloro-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl)-amide (480 mg) was added to a solution of K-tert. butylate (580 mg) in ethylene glycol (5 ml). The mixture was stirred at 11° C. for 72 h before it was diluted with water (100 ml), acidified with 10% aq. citric acid (13 ml). The resulting precipitate was collected, washed with water and diethyl ether and dried to give 2-phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl]-amide as a beige powder. LC-MS: tR=4.17 min, [M+1]+=491.24, [M−1]−=489.08.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:20])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
2.78 g of 4-octyloxybenzoic acid was added to 10 ml of benzene, and under stirring at room temperature, 2.36 g of PCl5 was added little by little. The mixture was then heated under reflux for 4 hours. Thereafter, the solvent was distilled off to obtain 4-octyloxybenzoic acid chloride.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]#[N:12])=[CH:6][C:4]=1[OH:5])#[N:2].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.CN(C=O)C>[CH2:13]([O:10][C:8]1[C:7]([C:11]#[N:12])=[CH:6][C:4]([OH:5])=[C:3]([C:1]#[N:2])[CH:9]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N#Cc1cc(O)c(C#N)cc1O
Reactant: CCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(C#N)c(O)cc1C#N
Temperature: 120 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
In a 300 ml-reaction vessel, 35.0 g (2.19×10-1M) of 2,5-dicyanohydroquinone, 23.8 g (1.44×10-1M) of n-hexylbromide, 20.0 g (1.45×10-1M) of potassium carbonate and 180 ml of DMF were placed, followed by stirring for 3 hours at 120° C. After the reaction, the reaction mixture was cooled and poured into 500 ml of 4N-hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent. The resultant residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to obtain 17.6 g of a crude product. The crude product was dissolved in ethanol and treated with activated carbon, followed by recrystallization from ethanol to obtain 8.2 g of 4-hexyloxy-2,5-dicyanophenol (Yield: 22.9%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)[CH3:2].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:30]>C(#N)C>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:10][CH:9]=1)=[S:13]
Reactant: Nc1nc2ccccc2s1
Reactant: CCC(CC)C(c1ccc(N=C=S)cc1)n1ccnc1
Solvent: CC#N
Product: CCC(CC)C(c1ccc(NC(=S)Nc2nc3ccccc3s2)cc1)n1ccnc1
Yield: 8.2 %

Procedure:
A mixture of 1-[2-ethyl-1-(4-isothiocyanatophenyl)butyl]-1H-imidazole (0.0123 mol) and 2-benzothiazolamine (0.0148 mol) in acetonitrile (80 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in H2O and CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The desired fractions were collected and the solvent was evaporated. The residue was purified again by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone and DIPE. The precipitate was filtered off and dried, yielding 0.44 g (9%) (±)-N-(2-benzothiazolyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-ethylbutyl]phenyl]-thiourea (compound 705).
Reaction SMILES: [CH3:1][O:2]C(Cl)Cl.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[OH:15])[CH3:7]>[Ti](Cl)(Cl)(Cl)Cl>[CH2:6]([C:8]1[C:9]([OH:15])=[CH:10][C:11]([CH3:14])=[C:12]([CH:13]=1)[CH:1]=[O:2])[CH3:7]
Reactant: COC(Cl)Cl
Reactant: CCc1ccc(C)cc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCc1cc(C=O)c(C)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
Titanium(IV) chloride (11 mL, 11 mmol, 1M in CH2Cl2) followed by dichloromethyl methyl ether (1.04 g, 9.1 mmol) was added to a cooled 0° C. solution of 2-ethyl-5-methyl-phenol (0.75 g, 5.5 mmol) The reaction mixture was stirred for 30 mins and then warmed up to rt and stirred for another 30 mins. The mixture was poured into ice and extracted with EtOAc. The organic layers were washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a purple oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave the title compound as an oil (0.45 g, 50%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3H), 2.60 (s, 3H), 2.65 (q, J=7.6 Hz, 2H), 5.37 (s, 1H), 6.62 (s, 1H), 7.62 (s, 1H), 10.11 (s, 1H).
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:31]=[C:30]5[C:25]([CH2:26][CH2:27][NH:28][CH2:29]5)=[CH:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:31]=[C:30]5[C:25]([CH2:26][CH2:27][N:28]([CH3:34])[CH2:29]5)=[CH:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3ccc4c(c3)CNCC4)cc3nccn23)cn1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCc2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-7-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 54; 10 mg, 0.024 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (49 mg, 0.49 mmol) and sodium triacetoxyborohydride (16 mg, 0.073 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=424.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:59][CH:60]([CH3:62])[CH3:61])[C:7]([F:58])=[C:8]([CH:10]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[N:56]=[C:55]([CH3:57])[O:54][N:53]=3)=[CH:48][CH:47]=2)[C:11]2[N:12]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:22]([OH:25])[CH2:23][CH3:24])[N:15]=2)[CH:9]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:59][CH:60]([CH3:62])[CH3:61])[C:7]([F:58])=[C:8]([CH:10]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[N:56]=[C:55]([CH3:57])[O:54][N:53]=3)=[CH:48][CH:47]=2)[C:11]2[N:12]([C:26]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22](=[O:25])[CH2:23][CH3:24])[N:15]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(O)CC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(=O)CC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of Intermediate 122.2 and Dess-Martin periodinate (60 mg, 0.12 mmol) in anhydrous CH2Cl2 (2 mL) was stirred at rt for 20 min. The reaction mixture was then partionated between EtOAc and 1 N NaOH, the organic layer was collected and dried over (Na2SO4), filtered and concentrated to afford Intermediate 122.3, which was used in the following step without further purification. LCMS (2 min gradient) RT=2.27 min, 826.4 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:23]([C:20]1[CH:19]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:21]=1[OH:22])[N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[CH3:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1ccc(CC(=O)O)cc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of a solution of 6.3 g (0.018 mole) of 4-[3,5-di-(tertiary-butyl)-4-hydroxyanilino]phenylacetic acid in 10 ml of N,N-dimethylformamide and 5 g (0.036 mole) of potassium carbonate was heated on a steam bath until gas evolution ceased. The mixture was allowed to cool to ambient temperature, and 5 milliliters of methyl iodide were then added. The mixture was heated at its boiling temperature and 5 ml aliquots of methyl iodide were added at 20, 45 and 60 minutes. After the mixture had evaporated, the residue was taken up in water and 2N sodium hydroxide solution was added. The mixture was warmed, and the insoluble residue of methyl 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methyl-anilino] phenylacetate was separated by filtration. The residue was suspended and partially dissolved in 50 ml of methanol, and 10 ml of 2.5N sodium hydroxide solution was added. The mixture was stirred for about 16 hours, diluted with 300 ml of water and 300 ml of diethyl ether, and was then further diluted with about 100 ml of hexane. The mixture was acidified with dilute hydrochloric acid and the aqueous phase was discarded. The organic phase was washed first with 10% sodium bicarbonate solution and then with 5% sodium carbonate solution. The product remained in the organic phase as the sodium salt. The organic phase was acidified with 10% aqueous hydrochloric acid and washed with sodium chloride solution, followed by drying. Evaporation provided a residue which was extracted with 20 ml of boiling benzene. Hexane (6 ml) was added, and the light yellow solid was recrystallized first from 80% aqueous ethanol, and then from benzene to provide fine yellow needles of 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methylanilino]phenylacetic acid, m.p. 181°-182.5° C. Analysis: Calculated for C23H31NO3 : % C, 74.8; % H, 8.5; % N, 3.8; Found: % C, 74.8; % H, 8.6; % N, 3.6.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10]([I:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1>C1COCC1>[C:1]([NH:5][C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10]([I:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cn1c(Cl)nc2c(I)cccc2c1=O
Solvent: C1CCOC1
Product: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Temperature: 50 °C
Yield: 89.7 %

Procedure:
A heterogeneous mixture of tert-butylamine (22.83 mL, 217 mmol) and 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700) (4.64 g, 14.48 mmol) in 2 mL of THF in a 100 mL RBF fitted with a reflux condenser was heated in an oil bath at 50° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the brown solid was dissolved in 300 mL of EtOAc, washed sequentially with 10 mL of water, 10 mL of sat. NaHCO3 solution and 10 mL of brine. The organic solution was concentrated. The residue was purified on a silica gel column (25-55% EtOAc in hexanes) to afford 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (4.64 g, 12.99 mmol, 90% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (1H, dd, J=7.5, 1.3 Hz), 7.93 (1H, dd, J=7.8, 1.2 Hz), 6.89 (1H, t, J=7.6 Hz), 6.02 (1H, s), 3.41 (3H, s), 1.60 (9H, s). m/z (ES, +ve) 358.1 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].O[C:6]([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=O)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](OCC)=[O:8]>C(O)C>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:17]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](=[O:8])[NH:3][N:4]=2)=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)OCC
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n[nH]c1=O
Yield: 78.6 %

Procedure:
1.69 g of hydrazine dihydrochloride were added, at a temperature in the region of 19° C., to 5.6 g of diethyl hydroxy[2-(4-benzyloxyphenyl)-2-oxoethyl]malonate dissolved in 180 cm3 of ethanol. The reaction medium was heated and maintained at reflux for 12 hours. After cooling, the solvent was removed under reduced pressure (2 kPa; 55° C.). The solid residue was triturated in 20 cm3 of ethanol, suction-filtered through a sinter funnel and oven-dried under reduced pressure (10 kPa; 50° C.). 3.85 g of ethyl 6-[4-(benzyloxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate were obtained in the form of a green solid melting at 239° C.