Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:34][CH3:35])([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][C:24]([CH2:34][CH3:35])([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:36])[NH:12][CH:11]2[C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[CH3:44])[C:9]1=[O:45])(=[O:48])[CH3:47]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reaction time: 2 h
Yield: 23.5 %

Procedure:
At room temperature, to a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methanesulfonylaminocarbonyl-propoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (400 mg, 0.58 mmol) and acetic anhydride (71 mg, 0.69 mmol) in DCM (20 mL) was added DMAP (7 mg, 0.06 mmol) slowly. After the mixture was stirred for 2 h, the solution was washed by 0.5N HCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (100 mg).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[CH3:26][C@H:27]1[O:32][C@H:31]([CH3:33])[CH2:30][NH:29][CH2:28]1.O>O1CCCC1>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][N:29]2[CH2:28][C@H:27]([CH3:26])[O:32][C@@H:31]([CH3:33])[CH2:30]2)[CH2:12]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C[C@@H]1CNC[C@@H](C)O1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(CC(=O)[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]23C)C[C@H](C)O1
Yield: 14 %

Procedure:
21-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (1 g.) was dissolved in dry tetrahydrofuran (50 ml.) and cis/trans-2,6-dimethylmorpholine (1 ml.) added to the solution. The mixture was refluxed for 4 hours. The mixture was poured into water, the emulsion extracted into ether, and the combined extracts washed with water, dried over anhydrous sodium sulphate and evaporated to a pale yellow foam (1.07 g.) which was purified by preparative T.L.C. in ethyl acetate. The faster running band (Rf ~0.6) gave 3α-hydroxy-21-(trans-2',6'-dimethylmorpholino)-5α-pregnane-11,20-dione (150 mg., 14%) as a white foam. [α]D + 70.5° (c 0.42).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18]Br)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].C(N(CC)CC)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CCCOc1ccc(C(=O)CBr)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1ccc(C(=O)CN2CCOCC2)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reaction time: 12 h
Yield: 39.2 %

Procedure:
The compound (150 mg, 0.32 mmol) of example 71 was dissolved in dichloromethane (20 ml), added with triethylamine (0.5 ml) and morpholine (40 mg, 0.46 mmol), followed by stirring for 12 h. The reaction mixture was washed orderly with water (10 ml) and saturated saline. The organic phase was dried with anhydrous Na2SO4, and concentrated under reduced pressure to give an oil, which was passed through a silica gel column to obtain the title compound (60 mg, yield: 39%). 1H NMR (CDCl3) δ: 11.20 (1H, br), 9.21 (1H, d), 8.17 (1H, dd), 7.15 (1H, d), 4.30 (2H, t), 3.75-3.64 (10H, br), 3.52 (1H, m), 2.03 (2H, m), 1.30 (6H, d), 1.16 (3H, t).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:13]([CH3:15])=[CH2:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]
Reactant: C=C(C)c1cccc2ccc(C#N)cc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccc2ccc(C#N)cc12
Reaction time: 1 h
Yield: 86.1 %

Procedure:
2-Cyano-8-isopropenylnaphthalene (0.23 g) and 10% palladium/carbon (containing 50% of water) (50 mg) were suspended in 20 ml of ethanol and the resulting suspension was subjected to catalytic hydrogenation at ordinary temperature under normal pressure for one hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated to giveacrudeproduct. This crude product was purified by silica gel column chromatography to give 0.20 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][CH2:8][C:7]1=[O:18]>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:20][O:19][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]1=[O:18]
Reactant: COc1ccc2c(c1)N(CCC(OC)OC)C(=O)CN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCC(OC)OC)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 71.7 %

Procedure:
In dichloromethane (10 ml) was dissolved 1-(3,3-dimethoxypropyl)-7-methoxy-3,4-dihydroquinoxalin-2(1H)one (201 mg, 0.717 mmol) under a nitrogen gas atmosphere, manganese dioxide (733 mg, 7.17 mmol) was added thereto at room temperature and the mixture was stirred at the same temperature for 17 hours. The insoluble material was removed by filtration using celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 143 mg (72%) of the title compound in the form of a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[CH:18]([CH3:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=1>C(O)C.[OH-].[K+].O>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:18]([CH3:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[NH:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(SCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Temperature: 55 °C

Procedure:
Dissolve 2-[[4-[3-[(6-amino-1-propyl-1,2,3,4-tetrahydro-3-propyl-2,4-dioxo-5-pyrimidinyl)amino]-2-methyl-3-oxopropyl]phenyl]thio]-acetic acid, 1,1-dimethylethyl ester (1.65 g, 3.18 mmol) in a mixture of ethanol (30 mL) and 15% potassium hydroxide (30 mL). Heat at 55° C. and stir for several hours. Cool, acidify and dilute with water (200 mL). Filter the precipitate and dry to give the title compound.
Reaction SMILES: ON=CC1C=CC([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[O:12])=CC=1.C[O-].[Na+].C(Br)C=C>O>[CH:18]([O:17][C:15]([CH2:14][NH:13][C:11](=[O:12])[NH2:10])=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)CNC(=O)Nc1ccc(C=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: CC(C)OC(=O)CNC(N)=O

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-isopropoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[4-allyloxyiminomethyl)phenyl]-N'-isopropoxycarbonylmethylurea.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: O=C1OCc2nc(CCCN3CCOCC3)ccc21

Procedure:
In a process similar to that described in Preparation 8, 3-(5-oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde and morpholine are reacted to provide the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C1COCC1>[S:1]1[C:5]([CH:21]([OH:22])[C:20]2[CH:19]=[CH:18][C:17]([N:16]([CH3:15])[CH3:25])=[CH:24][CH:23]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(O)c2cc3ccccc3s2)cc1

Procedure:
a-(2-benzo[b]thienyl)-4-dimethylaminobenzyl alcohol was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 8.9 mmoles, 5.3 ml), 4-dimethylaminobenzaldehyde (8.9 mmoles, 1.3 g) and THF (20 ml). The crude product (2.4 g) was carried forward without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH2:25]([N:27]([CH2:39][CH3:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:29]=1)[CH3:26].C(OC(=O)C)(=O)C>CO>[CH2:35]([N:34]([CH2:37][CH3:38])[C:30]1[CH:29]=[C:28]([N:27]([CH2:25][CH3:26])[CH2:39][CH3:40])[CH:33]=[CH:32][C:31]=1[C:7]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:24])[CH3:1])=[CH:23][CH:22]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:8]1)[CH3:36]
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1
Temperature: 91 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (16.28 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (9.68 g.) and acetic anhydride (10 ml.) was heated (at 91° C.) during two hours. Addition of methanol (20 ml., then 12 ml., then 10 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X= (CH3CH2)2N, Y2 = H, Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = Cl) in three fractions (m.p. 174°- 176° C., m.p. 180° -181° C. and m.p. 180° -181° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:35])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>O1CCOCC1>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:39][CH2:38][CH2:36][OH:37])[CH2:13][CH2:12]4)[C:16]3=[O:35])[C:32]([CH3:33])=[C:31]([F:34])[CH:30]=2)[CH2:29][CH2:28]1
Reactant: NCCO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Solvent: C1COCCO1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCNCCO)CC2)c1=O

Procedure:
3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 259d, 5 g) and ethanolamine (6.1 mL) were heated at 100° C. in dioxane (20 mL) in a sealed tube for 16 h. Purification of the cooled solution by preparative HPLC (Xterra column, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title product (2.95 g) after solvent removal and trituration with isohexane/diethyl ether (1:1 80 mL)
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[C:7]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2>C(O)C>[NH:2]([C:5]1[N:6]=[C:7]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)[NH2:3]
Reactant: NN
Reactant: Cc1cccnc1-c1cc2cccnc2c(Cl)n1
Solvent: O
Solvent: CCO
Product: Cc1cccnc1-c1cc2cccnc2c(NN)n1

Procedure:
To a solution of 98% hydrazine hydrate (7.4 g, 0.148 mol) in ethanol (100 mL) add 8-chloro-6-(3-methyl-2-pyridinyl)-1,7-naphthyridine (8.5 g, 0.0332 mol) and reflux for 2.5 hours. Concentrate the reaction mixture under reduced pressure, triturate the residual solid with water, filter and crystallize the isolated solid from benzene-petroleum ether to obtain the title compound, mp 115-6° C.
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][C:15]=3[CH2:30][CH3:31])=[CH:11][CH:12]=2)[N:7]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[N:6]=1)=[NH:4].[CH2:38]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH2:57])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)C>C(O)C>[CH2:38]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH:57][C:3]([C:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]4[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[CH:16][C:15]=4[CH2:30][CH3:31])=[CH:11][CH:12]=3)[N:7]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:6]=2)=[NH:4])[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)CC1N
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C(=N)OC)nn(C3CCCCO3)c2c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC1(OCC)CCN(Cc2ccccc2)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OCOCC[Si](C)(C)C)cc3CC)ccc12
Temperature: 50 °C
Yield: 45 %

Procedure:
To a solution of 6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 7, 17.15 g, 32.49 mmol) in ethanol (100 mL) was added a solution of 1-benzyl-4,4-diethoxy-piperidin-3-ylamine (Tetrahedron, 1995, 51, 13447-13454; 9.51 g, 34.2 mmol) in ethanol (70 mL). Acetic acid (3.56 mL, 62.1 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (400 mL) and saturated sodium hydrogen carbonate aqueous solution (300 mL). The organic layer was washed with further saturated sodium hydrogen carbonate aqueous solution (300 mL). The combined aqueous layers were re-extracted with EtOAc (400 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM:methanol:ammonia (80:20:2) to give the title compound (11.31 g) in a 45% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([N:2]2[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH:30]5[CH2:32][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=C(N[C@@H]1CCN(C(=O)C2(O)CC2)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=O.[Cl-].[OH:31][NH3+:32].N1C=CC=CC=1>C(O)C>[F:1][C:2]([F:29])([F:28])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)=[N:32][OH:31]
Reactant: [NH3+]O
Reactant: CCCCCCCCCCCCCCCCOc1ccc(C(=O)C(F)(F)F)cc1
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1ccc(C(=NO)C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
27 g (65.1 mmol) of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone are dissolved in 100 ml of ethanol. To the solution are added 4.5 g (65.1 mmol) of hydroxylammonium chloride and 12.9 g (163 mmol) of pyridine. The reaction mixture is refluxed for 4 hours, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, and extracted with ethyl acetate. The organic phase is washed with potassium hydrogen sulfate aqueous solution, water, and brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from hexane/toluene, yielding 13.5 g of 2,2,2-trifluoro-1-(4-hexadecyloxyphenyl)-ethanone oxime as a beige solid with a melting point of 76-80° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 0.88 (t, 3H), 1.20-1.40 (m, 24H), 1.40-1.50 (m, 2H), 1.75-1.84 (m, 2H), 3.96-4.02 (m, 2H), 6.89(E)/6.95(Z) (d, 2H), 7.43(E)/7.52(Z) (d, 2H), 8.28(Z)/8.43(E) (br s, 1H). The signals are tentatively assigned to the E- and Z-conformations. The spectrum indicates that the compound is a mixture of E- and Z-isomers. The ratio of the mixture is estimated to be E:Z=7:3.
Reaction SMILES: [C:1]([OH:17])(=O)[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([O:32][C:33](=[O:47])[CH:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[N:35]1[CH:39]=[C:38]([NH2:40])[N:37]=[CH:36]1)[CH3:31]>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:47])[CH:34]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[N:35]1[CH:39]=[C:38]([NH:40][C:1](=[O:17])[C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[OH:3])[N:37]=[CH:36]1)[CH3:31]
Reactant: CCCCCCC(C(=O)OCC)n1cnc(N)c1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)C(O)(c2ccccc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 4.6 g of benzilic acid, 3.2 g of 1,1'-carbonyldiimidazole, and 150 ml of DMF were mixed and stirred for 1 hour. A solution of 5.0 g of 4-amino-α-hexyl-1H-imidazole-1-acetic acid ethyl ester in DMF was added and the mixture stirred at room temperature over-night. The reaction mixture was concentrated in vacuo, ethyl acetate was added, and the organic solution was washed sequentially with water, a 10% sodium hydroxide solution, and water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by HPLC eluting with 30% ethyl acetate in toluene. The appropriate fractions were combined and concentrated in vacuo to provide 1.4 g of the desired titled product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C:15]([CH:28]([N:36]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:51])([CH3:4])([CH3:3])[CH3:2].Cl.O>CC(C)=O>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C:15]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:18])([F:17])[F:19])[CH:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[N:36]=2)=[CH:9][C:8]=1[CH3:51])=[O:52])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C2=NC(C(=O)OC(C)(C)C)C(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
Similarly, the reaction was carried out under similar conditions: To a solution of 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (426 mg, one diastereoisomer, obtained in example P12) in acetone (12 mL) was added hydrochloric acid (6 mL, 10%) and the solution was stirred at ambient temperature for 3 hours. Water was then added and the reaction mixture was extracted with ethylacetate and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 05% dichloromethane in heptane) to afford tert-butyl 5-(4-tert-butoxycarbonyl-3-methyl-phenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrole-2-carboxylate (248 mg) as a white solid. 19F NMR (376 MHz, CDCl3) δ −75.20 ppm (1 diastereoisomers). Chiral HPLC analysis (Chiralpack AS-RH, acetonitrile:water:methanol=55:5:40, 1 ml/min, retention time 22.87 minutes (minor enantiomer) and 25.52 minutes (major isomer) indicated that the reaction proceeded with little enantioselectivity.
Reaction SMILES: [O:1]([C:8](Cl)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][CH2:12][C:13]1([CH3:17])[CH2:16][O:15][CH2:14]1.CN1CCOCC1>C(Cl)Cl>[C:2]1([O:1][C:8]([O:11][CH2:12][C:13]2([CH3:17])[CH2:16][O:15][CH2:14]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC1(CO)COC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC1(COC(=O)Oc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A 0.552 mL (4.42 mmol) sample of phenoxycarbonylchloride in 2 mL of methylene chloride was added to a solution of 376 mg (3.68 mmol) of 3-hydroxymethyl-3-methyloxetane and 60.7 mL (5.52 mmol) of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The mixture was stirred at 0° C. for 3.5 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.582 g of the title compound, which was taken directly to the next step.