Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:18][C:17]2[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([OH:26])[CH3:25])[C:14](=[O:27])[N:13]([CH3:28])[C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:36]([O:26][C@H:24]([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][N:15]1[C:16](=[O:19])[C:17]2[NH:18][C:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]=2[N:13]([CH3:28])[C:14]1=[O:27])(=[O:38])[CH3:37]
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(COCc3ccccc3)nc2n(C)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(COCc3ccccc3)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a stirred solution of (R)-8-benzyloxymethyl-1-(5-hydroxyhexyl)-3-methylxanthine (19.9 g, 51.5 mmol), triethylamine (10.4 g, 103 mmol) and 4-dimethylaminopyridine (1.33 g, 11 mmol) in chloroform (130 ml) was added acetic anhydride (6.57 g, 64.4 mmol). After stirring for 3 hours at room temperature, the reaction mixture was quenched by addition of methanol (5 ml). The mixture was washed with aqueous potassium hydrogen sulfate solution (0.1 N) to pH 6-7, with water (2×50 ml) and with saturated aqueous sodium chloride solution (50 ml). After drying over magnesium sulfate, the organic solution was evaporated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-8-benzoxymethyl-3-methylxanthine (19.6 g, 88% yield) as white colored solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH:13]1([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[N:23][C:22]2[CH:24]=[CH:25][C:19]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:20][CH:21]=2)=[CH:4][CH:5]=1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C=Nc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99014.6 %

Procedure:
Methyl 4-formylbenzoate (47 g, 285 mmol) was dissolved in methanol (400 ml) and a solution of 4-cyclohexylaniline (50 g, 0.285 mmol) in methanol (200 ml) is slowly added with mechanical stirring. More methanol (1 l) was added and the suspension was stirred at room temperature for 3 days. Filtration, washing and drying in vacuo afforded 90.7 g (99%) of 4-[(4-cyclohexylphenylimino)methyl]benzoic acid methyl ester. This was dissolved in N-methylpyrrolidone (855 ml) and methanol (45 ml). With mechanical stirring sodium borohydride pellets (42.4 g, 1.12 mol) was added in portions keeping the temperature below 40° C. The mixture was then stirred at room temperature for 2 hours and at 40° C. for 16 hours. The mixture was cooled to 5° C. and water (2 I) was slowly added. Then acetone (350 ml) was added and the mixture was stirred at 5° C. for 1 hour. Filtration, washing with water (2×500 ml) and drying in vacuo afforded 78 g (86%) of 4-[(4-cyclohexylphenylamino)-methyl]benzoic acid methyl ester as a solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:22][C@@H:21]([OH:23])[CH2:20][C@@H:16]1[C:17]([OH:19])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl.CO>[OH:23][C@@H:21]1[CH2:22][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[C@@H:16]([C:17]([O:19][CH3:1])=[O:18])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
(Trimethylsilyl)diazomethane (2N solution in hexane, 2.9 ml) was added dropwise over 5 minutes to a stirred solution of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline (1.0 g) in DCM (20 ml) and methanol (5 ml) at room temperature until a permanent faint yellow colour persisted. The reaction mixture was concentrated in vacuo and purified by column chromatography, using 0-50% ethyl acetate in hexane as eluent, to give 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate as a clear oil (1.03 g, 97%); NMR spectrum (CDCl3) 4.90-4.37 (m, 2H), 3.73 (s, 3H), 3.64 (dd, 1H), 3.53-3.43 (m, 1H), 2.34-2.27 (m, 1H), 2.12-1.97 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH:28](O)=[O:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH:28]=[O:29])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: O=CO
Product: O=CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1

Procedure:
A solution of the amine from example 4 (300 mg, 0.79 mmol) in formic acid (15 ml) was stirred at 80° C. for 3 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and sodium bicarbonate solution. The layers were separated, and the organic phase was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH:21]([O:23]CC3C=CC=CC=3)[CH3:22])[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35](S([O-])(=O)=O)=[CH:34][CH:33]=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:42]([O:23][CH:21]([CH3:22])[CH2:20][CH2:19][C:18]1[O:31][C:14]2[C:15]3[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]=2[N:17]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)CCC(C)OCc3ccccc3)c(O)c21
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(CCC(C)OCc4ccccc4)oc3c21
Yield: 402.1 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-4-(benzyloxy)pentanamide (210 mg, 0.495 mmol) and pyridinium p-toluenesulfonate (24.8 mg, 0.0991 mmol) were heated under reflux in xylene (10 mL) for 14 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=30/70→60/40) to give the title compound (162 mg, yield 81%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[Hg]Cl)(=[O:3])[CH3:2].[Cl:13][C:14](=[CH2:17])[C:15]#[N:16].[BH4-].[Na+]>C(O)C>[C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[CH2:17][CH:14]([Cl:13])[C:15]#[N:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1[Hg]Cl
Reactant: C=C(Cl)C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N[C@@H]1CCCC[C@H]1CC(Cl)C#N
Temperature: 25 °C

Procedure:
31 g of trans-1-acetamido-2-chloromercuriocyclohexane are suspended in 250 ml of 95% strength ethanol: 187 ml (4 equivalents) of 2-chloroacrylonitrile are added. While cooling in ice, a solution of 3 g of sodium borohydride in 50 ml of ethanol is added as rapidly as possible. After warming up to room temperature, the precipitated elemental mercury is filtered off with suction over kieselguhr, thoroughly washed with ethanol and the filtrate is evaporated. The residue is taken up in methylene chloride, washed three times with 1N sodium hydroxide solution to destroy the boric esters, dried over sodium sulfate and evaporated. 13 g of the title compound are obtained as a yellow oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN[C@@H](C)C1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1C[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-[(3S*,5S*)-5-methylpyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f66) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([O:16]C)=[O:15])=[C:11]([CH3:18])[C:10]=1[C:19]#[N:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[C:11]([CH3:18])[C:10]=1[C:19]#[N:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(NC(=O)OC(C)(C)C)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc(NC(=O)OC(C)(C)C)c1C#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
The compound prepared in Example 221 (0.200 g) was suspended in methanol (10 mL) and aqueous sodium hydroxide solution (2 mol/L; 3.375 mL) was added and the reaction mixture stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a solid, which was dissolved in water, acidified to pH 1 and filtered to furnish the title compound (0.177 g) with the following physical properties.
Reaction SMILES: FC1C=CC(N)=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:10]([F:19])([F:20])[F:9])=[CH:12][CH:13]=1
Reactant: COC(C=O)OC
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1ccc(F)cc1
Agent: [Na+]
Product: COC(CNCc1ccc(C(F)(F)F)cc1)OC
Yield: 67 %

Procedure:
Following the procedure as described in step A of Preparation 2, making variations as required to replace 4-fluoroaniline with 4-(trifluoromethyl)benzylamine to react with dimethoxyacetaldehyde followed by the imine reduction with sodium triacetoxyborohydride, 2,2-dimethoxy-N-(4-(trifluoromethyl)benzyl)ethanamine was obtained in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 4.43 (t, J=2.7 Hz, 1H), 3.81 (s, 2H), 3.38 (s, 6H), 2.67 (dd, J=2.7, 2.5 Hz, 2H); MS (ES+) m/z 264.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH2:18][CH2:19][CH3:20])=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([NH2:16])=[O:15])=O)[CH3:2].[OH-].[Na+].OO.C(O)C>O>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[NH:16][C:14](=[O:15])[C:13]2[N:12]([CH3:17])[N:11]=[C:10]([CH2:18][CH2:19][CH3:20])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1ccccc1OCC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12

Procedure:
4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid was treated with 2N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1×700 ml; 3×200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3×400 ml) and brine (300 ml), then dried (Na2SO4) and evaporated under vacuum.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([CH3:41])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29](OC3C=CC([N+]([O-])=O)=CC=3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:30])[CH2:18]2)[CH3:41])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1COCCN1
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCOCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 420 and using the compound obtained in Example 362 and morpholine, the title compound was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH2:12])=[O:11].[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][CH:17]=[C:15]([CH2:14][Cl:13])[N:12]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cc2ccccc2o1
Product: ClCc1coc(-c2cc3ccccc3o2)n1
Yield: 30 %

Procedure:
In substantially the same manner as in Reference Example 47, 2-benzofurancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(2-benzofuranyl)-4-chloromethyloxazole. The yield was 30%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 133-134° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[Cl:20].[CH:22](OCC)(OCC)OCC>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=[CH:22]2)=[CH:7][C:6]=1[Cl:20]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)Cc1c(Cl)cc(Nc2ncccc2N)cc1Cl
Product: COC(=O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
A mixture of [4-(3-amino-pyridin-2-ylamino)-2,6-dichloro-phenyl]-acetic acid methyl ester (4.5 g, 13.8 mmol) and triethyl orthoformate (60 mL, 361 mmol, 26 equiv) is stirred for 13.5 h at reflux. The resulting mixture is allowed to cool to rt and concentrated in vacuo to provide the title compound as a dark solid: ES-MS: 336.0/338.0 [M+H]+; tR=4.58 min (System 1); Rf=0.28 (Hexane/EtOAc, 1:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5](=[O:16])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1Cl.[OH-].[K+]>O>[N+:12]([C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5](=[O:16])[C:6]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1Cl)N(CCO)CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1c2cc([N+](=O)[O-])ccc2OCCN1CCO
Temperature: 10 °C
Yield: 66.5 %

Procedure:
144.5 g of N,N-bis(2-hydroxyethyl)-2-chloro-5-nitrobenzamide in 500 ml of water containing 28 g of potassium hydroxide are heated for 2 hours with reflux cooling. The mixture is cooled to 10° C. and the precipitated, single-substance product is filtered off with suction and dried. 84 g of 7-nitro-4-(2-hydroxyethyl)-2,3-dihydro-1,4-benzoxazepin-5-one of melting point 151° C. are obtained. ##STR22##
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccccc2)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[C:58](=[O:59])[C:57]2[S:56][C:55]3[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=3[C:49]=2[CH:48]=[N:47]1)(=[O:27])[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:45][C:33]1[CH:32]=[C:31]([N:46]2[C:58](=[O:59])[C:57]3[S:56][C:55]4[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=4[C:49]=3[CH:48]=[N:47]2)[C:30]([CH2:29][O:28][C:25](=[O:27])[CH3:26])=[C:35]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:14]=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:34]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: C=CC(=O)NCCNc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C=CC(=O)NCCNc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 85 °C
Reaction time: 4 h
Yield: 30.4 %

Procedure:
A mixture of 105e (235 mg, 0.601 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 108c (299 mg, 0.601 mmol), Pd(dppf)Cl2(42.8 mg, 0.06 mmol) and K3PO4(382 mg, 1.80 mmol) in ACN (10 mL) and H2O (2 mL) was degassed and stirred at 85° C. for 4 h under nitrogen. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (EA/PE=4/1) to give N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]amino]ethyl]prop-2-enamide 105f (125 mg, 31%) as a brown solid. MS-ESI: [M+H]+ 684.3
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[C:15]1[N:20]=[C:19]([CH:21](O)[CH3:22])[CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH:21]([F:7])[CH3:22])[N:20]=1
Reactant: CC(O)c1cccc(C2OCCO2)n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(F)c1cccc(C2OCCO2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
0.81 ml of diethylamine trifluorosulfide (6.14 mmol) is added to a solution of 0.60 g of 1-(6-[1,3]-dioxolan-2-yl-pyridin-2-yl)ethanol (3.07 mmol) in 25 ml of dichloromethane cooled to -78° C. and maintained under a nitrogen atmosphere. The mixture is stirred for 30 minutes at -78° C. and then for 2 hours at room temperature. The mixture is poured slowly into a 10% aqueous solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated off. The title product is isolated by chromatography on a silica column (eluent: chloroform). 0.42 g of a yellow oil is obtained. Yield for the 2 stages combined: 53.4%
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(OCC)(=O)C.C(O)=O>C(N(CC)CC)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 25 °C

Procedure:
A reaction mixture containing 14.4 g (0.1 mol) of Meldrum's acid, 16.6 g (0.1 mol) of veratraldehyde, 100 ml of ethyl acetate and 25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 was heated to its boiling point during 1 hour and then refluxed for 6 hours. After distilling off the ethyl acetate under reduced pressure, the distillation residue was cooled to room temperature, 100 ml of water were added and the pH value of the mixture was adjusted to 1 with concentrated hydrochloric acid, then the method described in Example 1 was followed.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]([O:20][NH:21][CH3:22])([CH3:19])[CH3:18].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:21]([CH3:22])[O:20][CH:17]([CH3:19])[CH3:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: CNOC(C)C
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(N(C)OC(C)C)n1
Temperature: 100 °C
Yield: 41.1 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.65 g, 16.61 mmol), O-isopropyl-N-methyl-hydroxylamine hydrochloride (LXIII, 2.09 g, 16.61 mmol) and NaOH (0.66 g, 16.61 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was heated at 100° C. for 16 h. The volatiles were then removed under reduced pressure. Saturated NaHCO3 solution (50 mL) was added to the residue and the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV, 1.93 g, 95%). ESI-MS (m/z): 283 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.ClCC1C(C(F)(F)F)=NC=CC=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45].N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)OC2)C1=O>>[CH3:11][O:10][C:7]1[N:6]=[CH:5][C:4]([CH2:3][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C@@:26]3([C:44]4[C:35](=[CH:36][C:37]5[O:42][CH2:41][CH2:40][O:39][C:38]=5[CH:43]=4)[O:34][CH2:33]3)[C:25]2=[O:45])=[CH:9][N:8]=1
Reactant: COc1ncc(CCl)cn1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Cl
Agent: FC(F)(F)c1ncccc1CCl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: COc1ncc(CN2C(=O)[C@@]3(COc4cc5c(cc43)OCCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in Example 5.9 and making non-critical variations using 5-(chloromethyl)-2-methoxypyrimidine hydrochloride to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: mp 102-104° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 2H), 7.30-7.22 (m, 1H), 7.21-7.15 (m, 1H), 7.11-7.02 (m, 1H), 6.85-6.81 (m, 1H), 6.51 (s, 1H), 6.17 (s, 1H), 4.98-4.77 (m, 3H), 4.66-4.61 (m, 1H), 4.24-4.09 (m, 4H), 4.00 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 177.5, 165.4, 158.8, 155.2, 144.7, 141.2, 138.4, 132.2, 128.9, 124.3, 123.9, 122.7, 120.5, 111.4, 108.5, 99.5, 80.1, 64.5, 63.9, 57.9, 55.1, 38.9; MS (ES+) m/z 417.8 (M+1); Anal. Calcd for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07. Found: C, 65.94; H, 4.68; N, 9.77.