Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:6][N:7]([CH3:10])[C:8]#[N:9].[ClH:11]>O1CCOCC1.CCOCC>[ClH:11].[CH3:6][N:7]([CH3:10])[C:8]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[NH:9]
Reactant: CN(C)C#N
Reactant: c1cn[nH]c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)C(=N)n1cccn1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a solution of pyrazole (1.01 g, 14.8 mmol) and dimethylcyanamide (1.20 mL, 14.8 mmol) in 1,4-dioxane (15 mL) was added HCl (4.0 N in 1,4-dioxane, 3.8 mL, 15.2 mmol) and the resultant mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with dry ether (15 mL) to precipitate a yellow solid. The resultant precipitate was allowed to settle to the bottom of the flask (overnight) and the supernatant solution was decanted. The solid was dried under vacuum and provided the title compound (2.01 g, 78%). ES-MS m/z 139 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]([CH3:41])([C:34]([O:36]C(C)(C)C)=[O:35])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>C(Cl)Cl>[CH3:8][C:9]([CH3:41])([C:34]([OH:36])=[O:35])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCC(C)(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCOCCOCCOCCOCCOCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 114.7 %

Procedure:
TFA (1.5 mL, 19.3 mmol) was added dropwise to a stirred solution of tert-butyl 25,25-dimethyl-2,5,8,11,14,17,20,23-octaoxahexacosan-26-oate (58) (0.48 g, 0.97 mmol) in DCM (5 mL), and the reaction was stirred at RT for 4 h. The volatiles were removed in vacuo to afford 25,25-dimethyl-2,5,8,11,14,17,20,23-octaoxahexacosan-26-oic acid (59) (0.49 g, 95%) as a colourless oil: 1H NMR (400 MHz, CDCl3) δ: 3.68-3.60 (m, 26H), 3.55-3.52 (m, 2H), 3.47 (s, 2H), 3.36 (s, 3H), 1.18 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:10].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[Cl:18].Cl.C(NCC1C(O)=C(C2C=CC(Cl)=C(Cl)C=2)C=C(C2C=CC(Cl)=CC=2)C=1)(C)(C)C>>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=2[OH:10])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=Cc1cccc(Br)c1O
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)NCc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Product: O=Cc1cccc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
3′,4′-Dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared from 3-bromosalicylaldehyde and 3,4-dichlorophenylboronic acid using the same procedure described in Intermediate 5.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[N:61]=[C:62]=[O:63]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:62]([NH:61][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[F:54])=[O:63])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1F)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as the starting materials in 40% yield. LCMS for C31H32ClFN7O2 (M+H)+: m/z=588.1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH2:10][CH2:11][CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][CH2:11][CH3:12])[C:4](=[O:8])[CH:3]=1
Reactant: CCCBr
Reactant: O=c1cc(I)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1ccc(I)cc1=O
Temperature: 25 °C

Procedure:
To 2.0 g (9.05 mmol) 4-iodo-2-pyridone in 10 mL DMF are added 1.00 mL (10.9 mmol) 1-bromopropane and 3.13 g (22.6 mmol) K2CO3. The reaction mixture is stirred at r.t. over night. The reaction is quenched by the addition of water. The resulting mixture is extracted with EtOAc. The organic layer is washed with aq. NaHCO3 solution, dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, heptane/EtOAc. 70/30→50/50)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](=[S:19])[NH:7][C:6]=2[CH:17]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1c2ccc(Cl)cc2NC(=O)c2cscc21
Solvent: c1ccncc1
Product: CN1c2ccc(Cl)cc2NC(=S)c2cscc21
Reaction time: 18 h

Procedure:
A mixture of 0.5 g. of 7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5 ml. of dry pyridine is stirred and heated under reflux for 4 hours. The mixture is concentrated to dryness and is stirred with 10 ml. of 1N sodium carbonate solution for 18 hours. The precipitate is collected, washed with water and recrystallized from methanol to give a yellow solid, m.p. 238°-240°C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:15][CH2:16][N:18]([CH3:20])[CH3:19])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)N(C)C
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1CCN(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a solution of ethyl 3-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-5-carboxylate (1.16 g, 4 mmol) in THF (10 mL) was added 1M borane/THF (12 ml, 12 mmol) at 0° C. under Ar and stirring continued for 12 h at 60° C. The mixture was cooled to 0° C., quenched with 3M HCl solution and heated to 60° C. for 30 min. The mixture was basified with solid NaHCO3 to pH around 8 and the product was extracted with CHCl3 (2×30 ml). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo provided crude product. Purification by silica gel chromatography provided ethyl 3-tert-butyl-1-(2-(dimethylamino)ethyl)-1H-pyrazole-5-carboxylate as a pasty mass (0.47 g, 43% yield). 1H NMR (400 MHz, MeOH-d4): δ 6.73 (s, 1H), 4.66 (t, J 6.8 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 2.80 (t, J= 7.2 Hz, 2H), 2.34 (s, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.31 (s, 9H); MS (ESI) m/z: 268.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:27]3[CH2:28][O:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2n[nH]c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(CC3CO3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reaction time: 72 h
Yield: 56.1 %

Procedure:
To a solution of 3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (18.26 g, 53 mmol) and epichlorohydrin (41.12 mL, 526 mmol) in DMF (100 mL) was added cesium carbonate (20.56 g, 63 mmol). The reaction mixture was allowed to stir for 72 h, diluted with EtOAc (200 mL) and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to afford 3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (12.0 g, 57%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.68. MS (electrospray) m/z 491.2 (491.2, calculated for C27H31ClN6O, [M+H]+). 1H NMR (400 MHz, CDCl3) 7.55 (s, 1H), 7.36 (m, 2H), 4.61 (m, 2H), 4.38-4.47 (m, 1H), 4.11 (dd, J=14.3, 5.7 Hz, 1H), 3.67-3.79 (m, 2H), 3.34 (m, 1H), 2.83 (t, J=4.5 Hz, 1H), 2.75 (m, 2H), 2.51 (m, 1H), 2.41 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccccc1F

Procedure:
A mixture of ethyl 3-(2-fluorophenyl)propionate (25.54 g, 0.130 mol) and a 50% aqueous solution of sodium hydroxide (30 mL) in water (130 mL) was refluxed for 2 h. After cooling the mixture was washed with diethyl ether (2×100 mL). The aqueous phase was chilled in an ice bath, and the pH was adjusted to 3 with hydrochloric acid. The white precipitate which formed was collected by filtration, washed repeatedly with water, and dried in a vacuum at 60° C. for 18 h to give 18.66 g (85%) of 3-(2-fluorophenyl)prionic acid as a white solid; m.p., 72-74° C. This material was used without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]=[C:12]=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:48])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[CH:32][CH:31]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:48])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[O:13])=[CH:32][CH:31]=1)=[O:20])([CH3:16])([CH3:17])[CH3:15]
Reactant: CN1CCN(CCCNCc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Solvent: ClCCl
Product: CN1CCN(CCCN(Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C(=O)Nc2ccc3c(c2)OCCO3)CC1
Yield: 94 %

Procedure:
2,3-Dihydrobenzo[1,4]dioxin-6-ylisocyanate (0.11 mL, 0.80 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-4-[3-(4-methylpiperazin-1-yl)propylaminomethyl]benzamide (Reference Compound No. 4-1, 350 mg, 0.73 mmol) in anhydrous dichloromethane (15 mL), and then the reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-methanol) to give 460 mg of the title reference compound as a colorless amorphous product. (Yield 94%)
Reaction SMILES: [Br:1][C:2]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[C:20]([O:27][CH3:28])=[CH:19][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([NH:15][C:16](=[O:18])[CH3:17])=[N:9][C:10]=2[Cl:14].[H-].[Na+].[CH3:31]I>CN(C=O)C>[Br:1][C:2]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[C:20]([O:27][CH3:28])=[CH:19][C:3]=1[CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([N:15]([CH3:31])[C:16](=[O:18])[CH3:17])=[N:9][C:10]=2[Cl:14]
Reactant: COc1cc(Cn2cnc3c(Cl)nc(NC(C)=O)nc32)c(Br)c(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cn2cnc3c(Cl)nc(N(C)C(C)=O)nc32)c(Br)c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-yl]-acetamide and NaH in DMF was stirred at r.t. for 15 min, before adding MeI. Stirring was prolonged for 2 h at 50° C. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 6.422 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 6.80 (s, 1H), 5.45 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.57 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12]C(=O)C)[CH:9]=[C:8]([CH3:16])[C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=1)(=[O:3])[CH3:2].O1CCCC1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:16])[C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(OC(C)=O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)OCc1cc(O)cc(C)c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a solution of (4-acetoxy-3′-formyl-6-methylbiphenyl-2-yl)methyl acetate (1.63 g, 4.99 mmol) in a mixed solvent of tetrahydrofuran (10 mL) and methanol (5 mL) was added sodium borohydride (90%, 0.210 g, 5.00 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 3 hr under nitrogen atmosphere. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-80:20) to give the title compound (1.02 g, yield 71%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>CN(C=O)C>[N+:8]([C:7]1[C:2]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccn1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1ccccn1
Yield: 36 %

Procedure:
2-Chloro-3-nitropyridine (3.42 g, 21.60 mmol) and pyridine-2-ylamine (6.09 g, 0.65 mol) in DMF (20 mL) were stirred together at 80° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2 0-5% methanol in DCM) to give the title compound as an orange solid (1.68 g, 36%). LCMS (method H): Rt 1.45 min, [M+H]+ 217.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.FC1C=CC(C([O-])=O)=CC=1>O>[CH2:15]([O:14][C:12](=[O:13])[C:11]1[CH:17]=[CH:18][C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Agent: O=C([O-])c1ccc(F)cc1
Solvent: O
Product: CCOC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 97.8 %

Procedure:
A mixture of morpholine (12 g, 0.14 mol) and ethyl 4-fluorobenzoate (8 g, 0.04 mol) is heated at 120° C. The conversion of the 4-fluorobenzoate is complete after 24 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 9.2 g of pure 4-(4-morpholinyl) benzoic acid ethyl ester after recrystallisation from aqueous ethanol (50%, v/v). Yield: 89%. m.p. 82-83° C.; MS 235 (100, M+); H1 NMR (CDCl3): δ 7.93 (d, 21H), 6.86 (dd, 2H), 4.33 (q, 2H), 3.85 (t, 4H), 3.28 (t, 4H), 1.37 (t, 311); C13 NMR (CDCl3): δ 166.57, 154.14, 131.14, 120.70, 113.46, 66.60, 60.39, 47.75, 14.40.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[C:11]([CH3:12])=[CH:10][C@@H:9]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:32](=[O:34])[N:8]2[CH2:7][C@H:6]1[C:11]([CH3:12])=[CH:10][C@H:9]2[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 228.5 %

Procedure:
To a solution of O-allyl-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-4-methyl-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 12, 2 g, 6.40 mmol) and N,N-diisopropylethylamine (4.46 mL, 25.60 mmol) in acetonitrile (555 mL) at 0° C. was added triphosgene (0.760 g, 2.56 mmol) as a solution in acetonitrile (45 mL). The triphosgene solution was added via syringe pump at a rate of 0.1 mL/min. Once addition was complete the reaction was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The aqueous washes were found to contain some product and were extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and combined with previous extracts. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product (1.980 g, 91%) as a light orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:35][CH2:34]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][CH:33]([NH:32][C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:34][CH2:35]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: COc1ccc(NS(C)(=O)=O)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylsulfonamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:27]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:27])[C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C[C@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 60 °C
Yield: 59 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester (3.0 g, 8.2 mmol) was dissolved in acetonitrile (40 mL). Mixture was warmed to 60° C. N-Chlorosuccinimide (1.29 g, 9.7 mmol) was added to the warm solution. Reaction mixture was heated at reflux for 10 minutes. Mixture was cooled to room temperature then diluted with ethyl acetate (20 mL). Mixture was washed successively with saturated aqueous sodium bicarbonate (40 mL), and brine (20 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 59% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ 6.98 (s, 1H), 5.15 (d, J=3.3, 2H), 4.09 (m, 4H), 2.99 (m, 2H), 2.69 (m, 2H), 2.39 (dd, J1=4.8, J2=16.5, 1H), 2.17 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e (M−C2H4O2+H)+=340.0.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[Cl:12][CH2:13][CH2:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]>>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:16][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][Cl:12])[CH:3]=1
Reactant: N#Cc1cc(F)c(Br)cc1F
Reactant: O[C@H](CCCl)c1ccccc1
Product: N#Cc1cc(F)c(Br)cc1O[C@H](CCCl)c1ccccc1

Procedure:
This was prepared by the method of Example 43(a) using 4-bromo-2,5-difluorobenzonitrile and (R)-α-(2-chloroethyl)benzenemethanol.
Reaction SMILES: I[Si](C)(C)C.[C:6]([NH:14][C:15]1[S:16][CH2:17][C@@H:18]2[CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][C@:19]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:20]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[C:34]1([C@:19]23[CH2:21][NH:22][CH2:23][C@H:18]2[CH2:17][S:16][C:15]([NH:14][C:6](=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:20]3)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 399.4 %

Procedure:
Iodotrimethylsilane (10 mL, 70 mmol) is added to a solution of benzyl (4aR,7aS)-2-benzamido-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (11 g, 23 mmol) in acetonitrile (165 mL), stirred at room temperature for 2 hours and concentrated. The mixture is diluted with water (100 mL) and ethyl acetate (150 mL) and the pH adjusted to 4 with 1 M hydrochloric acid. The aqueous layer is collected. The pH of this aqueous layer is then adjusted to 10 with 2 M sodium hydroxide. The resulting solution is then extracted with ethyl acetate (100 mL), dried over magnesium sulfate and concentrated to give the title compound (31 g, 63%). ES/MS (m/e): 338 (M+H).
Reaction SMILES: CN(C)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](CN)=[CH:8][CH:7]=1.C1(O)C=CC=CC=1.C([Cl:25])CO.O(CCO)C1C=CC=CC=1.S(Cl)(Cl)=O>>[O:5]([CH2:4][CH2:3][Cl:25])[C:6]1[CH:13]=[CH:12][CH:9]=[CH:8][CH:7]=1
Reactant: OCCCl
Reactant: CN(C)CCOc1ccc(CN)cc1
Solvent: OCCOc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Oc1ccccc1
Product: ClCCOc1ccccc1

Procedure:
FR 2549828 discloses a multistage process for preparing 4-[2-(dimethylamino)ethoxy]benzylamine starting from phenol. Reaction of phenol with ethylenechlorohydrin initially delivers 2-phenoxyethanol which is reacted with thionyl chloride to give 2-phenoxyethyl chloride. After distilling this intermediate, it is reacted with acetamide and paraformaldehyde and then treated with mineral acid to give N-(2-chloroethoxybenzyl)acetamide. Reaction with dimethylamine then leads to N-[2-(dimethylamino)-ethoxy]acetamide, from which the desired product is released by acid hydrolysis. The process disclosed which has 6 separate process steps and an overall yield of 50% based on the phenol used is uneconomic.