Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.CN.C[CH2:15][N:16](C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:16][CH3:15]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
4-Bromo-2-fluoronitrobenzene (Aldrich, 1 eqvt), methylamine (2 eqvt), and hunig's base (3 eqvt) in DMF (1 Molar in substrate) were placed in a sealed vial and heated to 85° C. overnight. The crude mixture was diluted with water, and the product collected by filtration. Purification by chromatography (gradient: 92:8 hexanes:ethyl acetate to 68:32 hexanes:ethyl acetate) provided the title compound. 1HNMR (DMSO-d6, 400 MHz) δ 8.22 (bd, J=4.4 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.14 (d, J=2 Hz, 1H), 6.80 (dd, J=9.2, 2.4 Hz, 1H), 2.92 (d, J=4.8 Hz).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9](O)=[O:10])([O-:5])=[O:4].B(F)(F)F.CCOCC>C1COCC1>[N+:3]([C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)([O-:5])=[O:4]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a suspension of NaBH4 (2.85 g, 75.4 mmol) in dry THF (40 mL) at 0° C. was added a solution of 3,5-dinitrobenzoic acid (8.0 g, 37.7 mmol) in THF (20 mL), followed by the addition of BF3.OEt2 (12.5 mL, 98.0 mmol). The resulting mixture was warmed to 25° C. and stirred for 1 hour after which the reaction was quenched with 1 M HCl. The aqueous phase was extracted with DCM and the organic phase was then washed with saturated Na2CO3. The organic phase was dried over MgSO4 and evaporated under reduced pressure to give the title compound 6 as an orange solid (5.01 g, 25.3 mmol, 67%). 1H NMR (400 MHz, ((CD3)2C)) δ 8.91 (t, J=0.4 Hz, 1H), 8.57 (dd, J=1.2, 2.0 Hz, 2H), 4.93 (d, J=5.2 Hz, 2H), 3.57 (bs, 1H); 13C NMR (75 MHz, (CD3)2CO) δ 149.4, 148.4 (2C), 127.0 (2C), 117.6, 62.8; HRMS (ESI) Calculated for C7H5N2O5 [M−H]−: 197.0204. Found: 197.0200. m.p.: 89° C.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(Cl)(Cl)=O>C(O)CCC>[CH2:13]([O:14][C:13](=[O:15])[C@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[NH2:1])[CH2:2][CH2:3][CH3:4]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CCCCO
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Temperature: 100 °C
Yield: 181.9 %

Procedure:
L-Tryptophane (5 g; 24.5 mmol) and thionyl chloride (73.5 mmol; 5.3 ml) were dissolved in n-butanol (80 ml) and stirred at 100° C. over night. The product 5 precipitated after cooling to room temperature, was filtered off and washed with ice cold butanol and petrol ether. The product was dried at the oil pump, yielding 5.8 g of 5 (91%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:39])=[C:33]2[C:38]=1[O:37][CH2:36][CH2:35][CH2:34]2.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:31]1[C:32]([CH3:39])=[C:33]2[C:38](=[C:29]([F:28])[CH:30]=1)[O:37][CH2:36][CH2:35][CH2:34]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc(F)c4c(c3C)CCCO4)n2n1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.5 g, 9.20 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.22 g, 11.04 mmol) and 2N Na2CO3 (9.20 mL, 18.39 mmol) in DMF (100 mL) was degassed and flushed with N2 for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.744 g, 0.644 mmol) was then added and the reaction was flushed with N2 for another 15 min. The mixture was then heated at 100° C. for 16 h. At this point LCMS indicated completion of reaction and appearance of desired product. After cooling to rt, water was added (50 mL) and the mixture was extracted with ether (2×200 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was then purified by silica gel chromatography (5-60% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4 g, 7.58 mmol, 82% yield) as mixture of atrope isomers (approx 10% of minor atrope isomer was present). 1H NMR (500 MHz, CDCl3) δ 7.10 (s, 1H), 6.87 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.41 (qd, J=7.1, 3.1 Hz, 2H), 4.35 (dd, J=5.2, 4.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.80 (s, 3H), 2.79-2.73 (m, 2H), 2.23-2.15 (m, 2H), 1.82 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.22-1.19 (m, 4H), 1.18 (s, 9H). LCMS (M+H)=528.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C@@H:8]([OH:10])[CH3:9].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:10][C@H:8]([C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:11])[CH3:9])(=[O:22])=[O:21]
Reactant: C[C@H](O)c1c(Cl)cncc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](OS(C)(=O)=O)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve (S)-1-(3,5-dichloropyridin-4-yl)ethanol (5.02 g, 26.14 mmol) in dichloromethane (DCM, 100 mL) and cool the flask in an ice bath. Add triethylamine (TEA, 3.5 mL, 25.11 mmol) followed by the dropwise addition of methanesulfonyl chloride (2.2 mL, 28.42 mmol). Remove the ice bath and allow the reaction to warm to RT. After 4 hours, quench the reaction with water (100 mL) and separate layers. Extract the aqueous layer with DCM (50 mL) followed by 20% isopropyl alcohol (IPA)/chloroform (50 mL). Combine the organic extracts, dry over anhydrous sodium sulfate, filter and concentrate in vacuo. Yield: 7.15 g, (100%). MS (ES) m/z 270 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][N:11]([CH3:12])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[N:2]=2)[N:8]=1)=[O:14]
Reactant: CN(C)C(=O)Nc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 50 %

Procedure:
N′-(6-Cyano-2-pyridyl)-N,N-dimethylurea (0.72 g, 3.8 mmol) and methyl thiosalicylate (0.89 g, 5.2 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected and recrystallized from diisopropyl ether-methanol to give the titled compound (0.62 g, 50%) as white crystals.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C:8]3[S:15][CH:16]=[CH:17][C:7]=3[C:6]=2[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH3:28])[CH2:25][NH:26][CH3:27])=[CH:20][CH:19]=1.[CH2:29]=O>>[ClH:1].[CH3:29][N:26]([CH3:27])[CH2:25][C@@H:24]([C:21]1[CH:22]=[CH:23][C:18]([C:5]2[C:6]3[C:7]4[CH:17]=[CH:16][S:15][C:8]=4[C:9](=[O:14])[NH:10][C:11]=3[CH:12]=[CH:13][C:4]=2[OH:3])=[CH:19][CH:20]=1)[CH3:28]
Reactant: CNC[C@H](C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Reactant: C=O
Agent: Cl
Product: C[C@@H](CN(C)C)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 61.3 %

Procedure:
Following the procedure outlined for Example 1387, (R)-8-methoxy-9-(4-(1-(methylamino)propan-2-yl)phenyl)thieno[2,3-c]quinolin-4(5H)-one hydrochloride (40 mg, 0.11 mmol) was reacted with paraformaldehyde (7 mg, 0.21 mmol) and after purification the resulting material was converted to the hydrochloride salt as outlined in General Procedure D-2 to afford the desired product (28 mg, 67%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.65-7.52 (m, 3H), 7.44-7.32 (m, 3H), 7.18 (d, J=8.9 Hz, 1H), 6.12 (d, J=5.4 Hz, 1H), 3.62 (d, J=3.1 Hz, 1H), 3.46 (dd, J=13.2, 4.7 Hz, 2H), 2.97 (s, 3H), 2.94 (s, 3H), 1.49 (d, J=6.6 Hz, 3H); ESI MS m/z 379 [C22H22N2O2S+H]+; HPLC >99% (AUC), tR=8.57 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[K].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[OH:20]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: [K]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1Cl

Procedure:
A stirred solution of 2,4-dichlorobenzonitrile (51.6 g., 0.03 mole) and the potassium salt of 2,4-dichlorophenol (60.3 g., 0.03 mole) in 250 ml. of dimethyl acetamide was heated for 24 hours at 120° C. The cooled reaction mixture was diluted with 1000 ml. of water and the resultant oil was extracted with ether. Evaporation of the ether solution gave 88.0 g. of brown oil. Analysis by v.p.c. showed a 2:1 mixture of the desired compound and the isomeric 4-chloro-2-(2',4'-dichlorophenoxy) benzonitrile. A series of fractional crystallizations from 60°-110° C. petroleum ether gave the desired 2-chloro-4-(2',4'-dichlorophenoxy)benzonitrile with a melting point of 69°-74° C. The minor isomeric by-product melted at 110°-113° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1F.CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)OC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)OC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 91.4 μmol) was dissolved in DMF (190 μL). NaH (2.6 mg, 109.7 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (21.4 μL, 182.9 mmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (949 μL, 1.1 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt oil (29.5 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO2, 318.10. found 318.0.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38]1[NH:39][C:40](=[O:43])[NH:41][N:42]=1>CN(C=O)C.O>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:37][C:38]2[NH:39][C:40](=[O:43])[NH:41][N:42]=2)[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=c1[nH]nc(CCl)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]nc(CN2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a mixed solution of the compound (0.15 g) obtained in Example 1 and potassium carbonate (0.047 g) in DMF (2 ml) and water (0.02 ml), 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.046 g) synthesized by the method described in the document (e.g., Tetrahedron Letters, Vol. 41, pages 8661-8664) was added at 0° C., and the reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound as colorless crystals (0.050 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH:26]([O:25][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:31][CH:30]=3)[CH2:27]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1ccc(OC2CN(c3nc(Cl)ncc3F)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution 2,4-dichloro-5-fluoropyrimidine (150.0 mg, 0.898 mmol) in 2-propanol (4.00 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (0.469 mL, 2.70 mmol) followed by 3-(4-fluorophenoxy)azetidine hydrochloride (183 mg, 0.898 mmol). The resulting reaction mixture was stirred at RT for 1 h and concentrated. Purification of the crude using MPLC (25 g cartridge, 40 g column, 0 to 60% EtOAc-hexanes) gave 2-chloro-5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (240.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH2:38](Br)[CH:39]=[CH2:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:40][CH:39]=[CH2:38])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: C=CCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: C=CCOc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with allyl bromide
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16]3[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[N:21]=[C:16]([N:12]2[CH2:13][CH:14]3[CH:10]([CH2:9][NH:8][CH2:15]3)[CH2:11]2)[N:17]=1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Yield: 96.4 %

Procedure:
5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (0.92 g, 2.9 mmol), DCM (10 mL) and TFA (5 mL) were stirred at 23° C. for 2 h. The mixture was concentrated to remove the volatiles, diluted with EtOAc and 1N aq. NaOH, and extracted with EtOAc (3×). The organic fractions were dried and concentrated to give the title compound (0.61 g, 96%) that contained a small amount of DCM and was used as is. MS (ESI) mass calcd. for C12H18N4, 218.30; m/z found, 219.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 6.27 (s, 1H), 3.81-3.70 (m, 2H), 3.55-3.48 (m, 2H), 3.16-3.07 (m, 2H), 2.94-2.78 (m, 4H), 2.29 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5]1=[O:11].[NH2:12][C:13]1[C:29]([Cl:30])=[CH:28][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]2[O:26][CH3:27])=[O:18])=[C:15]([O:31][CH3:32])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:12][C:13]1[C:29]([Cl:30])=[CH:28][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5]3=[O:11])[CH2:22][C@H:21]2[O:26][CH3:27])=[O:18])=[C:15]([O:31][CH3:32])[CH:14]=1
Reactant: CCN1CCN(CCCl)C1=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(CCN2CC[C@H](NC(=O)c3cc(Cl)c(N)cc3OC)[C@H](OC)C2)C1=O
Temperature: 70 °C
Yield: 67.8 %

Procedure:
A mixture of 2.21 parts of 1-(2-chloroethyl)-3-ethyl-2-imidazolidinone, 3.13 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 1.58 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated for 48 hours at 70° C. The reaction mixture was evaporated. Water was added and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.08 parts (67.8%) of cis-4-amino-5-chloro-N-[1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 152.8° C. (compound 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-2-methylpropanoate (6 g, 29 mmol), KOH (3 g, 57 mmol) and 100 mL EtOH/H2O (4:1) was refluxed for 4 hours. The mixture was cooled to room temperature. The mixture was extracted with EtOAc and the organic layer discarded. The water layer was acidified with concentrated HCl, extracted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3.1 g of the product as a white solid. MS m/e=211(M−1)−.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:27][CH2:26][CH2:25][C@H:8]3[S:9](=[O:24])(=[O:23])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:12][C@:7]3([CH3:28])[C:6]=2[CH:29]=1.[Cl:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1>>[Cl:30][C:31]1[N:32]=[CH:33][C:34]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:27][CH2:26][CH2:25][C@H:8]4[S:9](=[O:23])(=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[N:12][C@:7]4([CH3:28])[C:6]=3[CH:29]=2)=[O:38])=[N:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reactant: O=C(O)c1cnc(Cl)cn1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4cnc(Cl)cn4)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Yield: 70.1 %

Procedure:
Using general method 3 (step 1), trans intermediate 19 (150 mg, 0.354 mmol) and 5-chloropyrazine-2-carboxylic acid (67.4 mg, 0.425 mmol) were combined to afford the title compound (140 mg, 0.248 mmol, 70.1%) as a white solid. MS m/z=564.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:14])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(F)cc1O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(F)ccc1C(C)=O
Temperature: 75 °C
Yield: 103.1 %

Procedure:
1-(4-fluoro-2-hydroxyphenyl)ethanone (12.0 g, 77.9 mmol), iodomethane (6.38 ml, 101 mmol), potassiumcarbonate (14.0 g, 101 mmol) were heated at 75° C. in ACN (200 ml) for 8 h. The reaction mixture was brought to ambient temperature, filtered and then evaporated under reduced pressure to dryness. New ACN (150 ml), iodomethane (2 ml, 32 mmol) and potassiumcarbonate (4 g, 29 mmol) was added. The reaction mixture was heated at 75° C. for 3 h. The reaction mixture was concentrated, EtOAc (100 ml) was added and the mixture was filtered and evaporated to give the title product (13.5 g, 100%). MS m/z (rel. intensity, 70 eV) 168 (M+, 11), 153 (bp), 110 (23), 95 (21), 82 (12).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[S:10]1[C:14]2[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1>>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][S:10][C:14]=2[CH:15]=1)(=[O:20])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: Cc1ccc(N)c(Br)c1
Product: Cc1ccc(NS(=O)(=O)c2ccc3ncsc3c2)c(Br)c1

Procedure:
By following a procedure analogous to Example 3 starting from 2-bromo-4-methylaniline and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange solid (yield=76%).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1>O1CCCC1.O>[Cl:16][C:17]1[CH:22]=[C:21]([O:13][CH:10]2[CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: OC1COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(CSc2nc(Cl)cc(OC3COC(c4ccccc4)OC3)n2)c1F

Procedure:
To a solution of 2-phenyl-1,3-dioxan-5-ol (484 mg) in anhydrous tetrahydrofuran (10 ml) at 0° C. was added 60% sodium hydride (110 mg) and the mixture was heated to reflux for 25 minutes. On allowing to cool to ambient temperature 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of step (ii) (75 mg) was added and the reaction was heated to reflux for a further 90 minutes. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate (×3). The combined organic layers were dried with magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 95:5 to 90:10 mixture of iso-hexane and ethyl acetate as eluent to give the sub-title compound as a white solid. Yield: 350 mg