Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][C:2]1=[CH:6][CH:7]=[CH:8]N.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH3:12][CH:11]1[CH2:7][CH:6]=[CH:2][CH2:3][CH2:4][CH:5]=[CH:8][CH2:7][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:10]1
Reactant: C=CCN
Reactant: NC=CC=C1CC=CO1
Product: CC1C=NC(c2ccco2)CC=CCCC=CC1

Procedure:
The procedure described in Example 1(a) is repeated, except that 273 g (2.02 mols) of N-2-furylidenepropenylamine [prepared by reaction of 2-furylaldehyde with allylamine and subsequent isomerisation in the presence of potassium tert.-butylate; boiling point 60°-62° C./67 Pa; nD20 =1.6004] are used. Distillation yields 210 g (0.865 mol) of 3-methyl-12-(2-furyl)-1-aza-1,5,9-cyclododecatriene; boiling point 106°-108° C./4 Pa; nD20 =1.5260.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH:16]([F:29])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[F:29][CH:16]([F:15])[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH3:18]
Reactant: CC(c1ccc(S(=O)(=O)Cl)cc1)C(F)F
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C(F)F)cc3)cc2)C1
Yield: 12.6 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (150 mg, 0.78 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-(2,2-difluoro-1-methyl-ethyl)-benzenesulfonyl chloride (321 mg, 1.26 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (40 mg, 18%) as a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH2:20]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:19])C)[CH3:2].[CH:23]([N:36]1[CH2:39][C:38](OS(C)(=O)=O)([CH3:40])[CH2:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:18][C:38]3([CH3:40])[CH2:39][N:36]([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37]3)[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:19])[CH3:20])[CH3:2]
Reactant: CCOC(=O)C(C)(CC)N1C(=O)COc2cc(F)c(O)cc21
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC3(C)CN(C(c4ccccc4)c4ccccc4)C3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A mixture of ethyl 2-(7-fluoro-6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.200 g, 0.706 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (Preparation #3, Step B, 0.257 g, 0.777 mmol) and Cs2CO3 (0.460 g, 1.412 mmol) in DMF (8 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give 2-[7-fluoro-6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester as a white solid (0.280 g, 76%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.31 (m, 2H), 7.29 (m, 2H), 7.27 (m, 2H), 6.87 (d, J=10.4 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 5.45 (q, J=7.2 Hz, 1H), 4.55 (d, J=15.2 Hz, 2H), 4.41 (s, 1H), 3.98 (q, J=7.2 Hz, 2H), 3.34 (d, J=7.6 Hz, 2H), 3.19 (d, J=7.6 Hz, 2H), 1.59 (s, 3H), 1.56 (d, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([C:34](O)=[O:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([C:34]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]4[C@@H:16]3[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]4[CH2:9][CH2:10][C:11]3=[O:21])[CH2:3]2)=[O:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Product: CC(C)(C)OC(=O)N1CC(C(=O)O[C@H]2CC[C@@]3(C)C(C2)C(=O)C[C@@H]2[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]23)C1
Yield: 65 %

Procedure:
Prepared in 65% yield from 3β-hydroxyandrostane-6,17-dione and 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid by the procedure described in Prepn. 43. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.66 (1H, m), 4.50-1.00 (29H, m), 1.35 (9H, s), 0.78 (3H, s), 0.69 (3H, s).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.[Pt](=O)=O>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccnc(-c2cccc(C(F)(F)F)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(c2cccc(C(F)(F)F)c2)C1
Reaction time: 3 h
Yield: 52.7 %

Procedure:
Methyl 2-(3-(trifluoromethyl)phenyl)isonicotinate (2.6 g, 9.25 mmol) was dissolved in acetic acid (40 mL) and platinum(IV) oxide (0.210 g, 0.92 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 3 h. The catalyst was filtered off, washed with MeOH and the eluate evaporated. DCM and 1 M K2CO3 were added and the phases separated. The organic layer was washed with brine, passed through a phase separator and evaporated to yield methyl 2-(3-(trifluoromethyl)phenyl)piperidine-4-carboxylate (1.4 g, 52%) as a slightly brown oil. MS m/z 288 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:30])C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11]([CH3:12])=[O:30])=[N:6]2
Reactant: CSc1ncc2c(Br)cc(-c3ccccc3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2c(Br)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Into a Round bottom flask, [A] 5-Bromo-2-methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine (0.30 g, 0.00094 mol) and Methylene chloride (2 mL, 0.03 mol) were added. m-Chloroperbenzoic acid (0.178 g, 0.00103 mol) was added portion wise over 20 minutes. The reaction was stirred at room temperature for one hour. The reaction was partitioned with DCM (200 mL) and saturated NaHCO3 (200 mL). The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The solid was washed with hexane to give 5-Bromo-2-methanesulfinyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (270 mg, 86%). NMR 1H (DSMO-d6)-9.24 (s, 1H), 8.24 (d, 2H, J=7.44 Hz), 7.92 (s, 1H), 7.56 (t, 2H, J=7.93 Hz), 7.47 (t, 1H, J=7.32 Hz), 2.98 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.[C-]#N.[K+].S(Cl)(Cl)=O.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24])=[O:14]
Reactant: CCCNCCC
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)C(=O)Cc1cccc([N+](=O)[O-])c1C

Procedure:
Alternative process for the preparation of Ropinirole is described in J. Med. Chem. 1985, 28, 1533-1536 as shown in Scheme-2. The process comprises, the reduction 2-Methyl-3-nitro-benzoic acid (VIII) with diborane to carbinol of formula (IX). The carbinol compound (IX) is chlorinated with thionyl chloride in pyridine to give highly lachrymatory compound of formula (X), which is further converted to compound of formula (XII) by reaction with Potassium cyanide and followed by hydrolysis. 2-methyl-3-nitrophenyl acetic acid (XII) is converted to its acid chloride with thionyl chloride and treated with Di-n-propylamine to give 2-Methyl-3-nitrophenyl-N,N-di-n-propyl acetamide of formula (IV). The compound of formula (IV) is further reduced with borane in THF under reflux to give 2-Methyl-3-nitrophenylethyl-N,N-di-n-propyl amine (V). The amine of formula (V) is reacted with potassium metal in Ethanol and diethyl oxalate resulting in compound (VI) (where R=H), which is treated with hydrogen peroxide, NaOH and HCl to give the intermediate 2-Nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII). This intermediate is hydrogenated on palladium/carbon in ethanol to give desired compound Ropinirole hydrochloride of formula (Ia)
Reaction SMILES: [Br:1]Br.C([NH:7][S:8]([C:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]([C:21]2[C:25]([CH3:26])=[CH:24][S:23][C:22]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:13][CH:12]=1)(=[O:10])=[O:9])(C)(C)C>ClCCl>[Br:1][C:24]1[S:23][C:22]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[C:11]([S:8](=[O:10])(=[O:9])[NH2:7])=[CH:12][CH:13]=2)[C:25]=1[CH3:26]
Reactant: BrBr
Reactant: COC(=O)c1scc(C)c1-c1ccc(S(=O)(=O)NC(C)(C)C)c2c1CCCC2
Solvent: ClCCl
Product: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Bromine (0.045 g, 0.015 ml, 0.28 mmol) was added dropwise to a stirred suspension of methyl 3-(4-(N-(tert-butyl)sulfamoyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-4-methylthiophene-2-carboxylate (59c, 0.10 g, 0.24 mmol) in 15 ml dichloromethane at a temperature of about 0° C. The reaction mixture was then stirred at about 25° C. for 2 hours. the progress of the reaction was monitored by TLC. The reaction mixture was then concentrated. 20 ml of dichloromethane was added to the residue so obtained. The mixture so formed was washed with water (2×10 ml), brine (1×10 ml) and the organic layer so obtained was dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.08 g, 67.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[N:16][N:17]([CH:18]([CH3:20])[CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br:23]Br>C(O)(=O)C>[Br:23][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:22]=[CH:21][C:14]2[N:15]=[N:16][N:17]([CH:18]([CH3:19])[CH3:20])[C:13]=2[CH:12]=1)=[O:10]
Reactant: BrBr
Reactant: CC(C)n1nnc2ccc(C(=O)Cc3ccc(F)cc3)cc21
Solvent: CC(=O)O
Product: CC(C)n1nnc2ccc(C(=O)C(Br)c3ccc(F)cc3)cc21
Temperature: 50 °C

Procedure:
To a stirred solution of 191 mg of 2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone in 2 mL of acetic acid was added 0.64 mL of bromine (1 M in acetic acid). The mixture was heated at 50° C. for 3 hours. The reaction mixture was cooled to 22° C. and concentrated to dryness. The residue was taken-up into ethyl acetate and washed with saturated aqueous sodium bicarbonate, brine; the organic layer was dried (sodium sulfate), filtered and the filtrate was concentrated to give 222 mg of 2-bromo-2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone as a light yellow oil. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)=[O:25]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:18][C:19]([O:21][CH2:23][C:24](=[O:25])[C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=2)=[O:20])[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)CCCOC1
Product: O=C(CC1(NC(=O)OCc2ccccc2)CCCOC1)OCC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Prepared by Method F using (3-{[(benzyloxy)carbonyl]amino}tetrahydro-2H-pyran-3-yl)-acetic acid (Preparation 23, 0.6 g, 2.05 mmol) and 2-bromo-1-[4-(trifluoromethoxy)-phenyl]ethanone (0.579 g, 0.205 mmol). The reaction was stirred at 50° C. for 1.5 hours.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C@H:12]([CH2:13][CH:14]=C)[CH2:11][CH2:10][C:9]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[O:20]=[O+][O-]>CO>[O:16]=[C:9]1[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@H:12]([CH2:13][CH:14]=[O:20])[CH2:11][CH2:10]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1CCC(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=CC[C@@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 8 h

Procedure:
A solution of (S)-1-(phenylmethyl)-5-(2-propenyl)-2-pyrrolidinone (44.8 g, 0.208 mol) in 800 mL of 1:1 methanol:methylene chloride was cooled to -78° C. and was ozonized using a Welsbach ozonizer for 6.5 h, approximately 1 h longer than the time required to observe a light blue color of ozone in the solution. Excess ozone was flushed out of the system with oxygen, and the solution was treated with methyl sulfide (80 mL). The solution was then allowed to come to room temperature and to stand overnight. The solvents were removed on a rotary evaporator, and the residual liquid was dissolved in 700 mL of methylene chloride, washed with water, and dried over Na2SO4. Evaporation of the solvent afforded 43.0 g of crude (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidineacetaldehyde. Chromatography on silica gel (1 kg) eluting with 4% methanol in methylene chloride afforded 38 g (84.4% yield) of the pure (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidineacetaldehyde. 1H NMR (CDCl3) δ 1.60-2.60 (m, 4 H, CH2), 2.77 (half of ABX, 1 H, Jgem =18,Jvic =4 Hz, CH2CHO), 3.98 (m, 1 H, NCH), 4.10 and 4.82 (AB, 2 H,Jgem =15 Hz, CH2Ph), 7.15-7.40 (m, 5 H, phenyl), 9.65 (s, 1 H, CHO).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11])#[N:13]
Reactant: CN=C(NC#N)SC
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CC#N
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N

Procedure:
A solution of 17.0 g of 4-(2-aminoethyl)thiomethyl-5-methylimidazole and 11.2 g of N-cyano-N',S-dimethylisothiourea in 500 ml of acetonitrile was refluxed for 24 hours. The mixture was concentrated and the residue was chromatographed on a column of silica gel with acetonitrile as eluant. The product obtained was recrystallized from acetonitrile-ether to give N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p. 141°-142°.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(O)(=O)CC[C:13]([OH:15])=[O:14]>>[C:13]([OH:15])(=[O:14])[CH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCC(=O)O
Reactant: O=C(O)CCCC(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
The mother liquor with the urea-succinic acid adduct removed was treated with AMBERLYST 15 to remove urea and cooled to and allowed to stand at 15° C. after 200 g. of methanol had been distilled off, to deposit crude adipic acid. By subjecting the solution to filtration, 11.0 g. of crude adipic acid was obtained. The obtained crude adipic acid contained 1.8% by weight of glutaric acid and 1.6% by weight of succinic acid. This crude adipic acid may be recycled to a purification step in the production of adipic acid to obtain pure adipic acid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1([C:23]#N)[CH2:22][CH2:21][CH2:20]1.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1([CH:23]=[O:28])[CH2:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2ccccc2C(F)(F)F)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccccc2C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.7 ml of diisobutylaluminum hydride was added dropwise over 2 hours to a solution of 8.5 g of 1-(2-trifluoromethyl-phenyl)-cyclobutanecarbonitrile in 85 ml toluene at 0° C. After addition, the ice-water bath was allowed to warm up to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 200 ml of 5% sulfuric acid in ice-water, and stirred for 10 minutes. The mixture was extracted four times with ether. The combined ether extracts were dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 5%) to yield 6.2 g of product.
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([NH2:24])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[CH:4]=[N:24][C:13]1[C:14]([C:16]#[C:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:15][C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(N)c(C#Cc2ccccc2)n1
Solvent: Cc1ccccc1
Product: Cc1ccc(N=CN(C)C)c(C#Cc2ccccc2)n1
Yield: 18.4 %

Procedure:
A solution of N,N-dimethylformamidedimethylacetal (80 μl, 0.60 mmol) and (6-methyl-2-phenylethynyl-pyridin-3-yl)amine (102 mg, 0.49 mmol) from Example 1, in toluene (1 ml) was heated for 20 h, at 80° C. The solvent was evaporated and the residue was purified by flash chromatography (hexane/ethyl acetate 4:1) to give 24 mg (0.09 mmol, 15%) of N,N-dimethyl-N′-(6-methyl-2-phenylethynyl-pyridin-3-yl)-formamidine as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7].C(N)(=[S:15])C>Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]([NH2:7])=[S:15]
Reactant: CC(N)=S
Reactant: COc1ccc(C#N)cc1OC
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=S)cc1OC
Temperature: 90 °C
Yield: 61.9 %

Procedure:
25 g of 3,4-dimethyoxybenzonitrile and 23 g of thioacetamide were dissolved in 120 ml of 10% hydrochloric acid-DMF. The solution was heated at 90° C. for 3 hours. The solution was further heated at 130° C. for 5 hours to conduct a reaction. The solvent was removed by distillation. The residue was washed twice with 100 ml of diethyl ether. Similar washing was conducted with 100 ml of water. The resulting crystals were collected by filtration and dried. Recrystallization from methanol was conducted to obtain 18.7 g of 3,4-dimethoxythiobenzamide as light brown columnar crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26]C)[CH:20]=1>>[CH3:26][NH:25][C:21]1[CH:20]=[C:19]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:12][CH:13]=2)[N:24]=[CH:23][N:22]=1
Reactant: CCNc1cc(Cl)ncn1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Product: CNc1cc(Nc2ccc(OCCN3CCN(C)CC3)cc2)ncn1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
The title compound is prepared as described in Example 160A but using 4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (500 mg, 2.13 mmol, 1 eq.), (6-chloro-pyrimidin-4-yl)-ethyl-amine and stirring the reaction mixture at 150° C. for 20 h. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) followed by trituration in diethyl ether affords 250 mg of the title compound as a white solid: ESI-MS: 343.2 [MH]+; tR=1.00 min (gradient J); TLC: Rf=0.23 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[N:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19]C)=[O:18])[N:14]=2)=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[N:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([OH:19])=[O:18])[N:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cccnc1-c1csc(-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccnc1-c1csc(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
5.5 ml of a 2N NaOH solution were added to a solution of methyl 2-(2-(4-fluorophenyl)thiazol-4-yl)nicotinate (850 mg, 2.7 mmol) in 30 ml of methanol, and afterwards stirred for 4 hours at 50° C. The reaction mixture was evaporated to dryness, mixed with water and neutralized by adding 2N HCl. Filtration with suction and drying the precipitate formed resulted in 690 mg of the acid as amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:19].Cl.[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([NH2:31])=[NH:30])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[ClH:19].[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[NH:30])[NH2:31])[CH2:25][CH2:24]1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: N=C(N)N1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCC1CCN(C(=N)N)CC1)C1CCCCC1

Procedure:
The title compound was prepared using (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (10.1 g, 39.28 mmol), 4-aminomethyl-piperidine-1-carboxamidine dihydrochloride (9.0 g, 39.28 mmol) , HATU (14.9 g, 39.28 mmol), and collidine (15.6 ml, 117.8 mmol) in dimethylformamide as described in example 223 a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Nc1ncc(Cl)cc1I
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 169.6 %

Procedure:
A stirred solution of 5-chloro-pyridin-2-ylamine (51.4 g, 0.40 mol) in 2M sulfuric acid (700 mL) was treated portionwise with potassium iodate (43.7 g, 0.2 mol) and the mixture heated to 100° C. A solution of potassium iodide (36.5 g, 0.55 mol) in water (100 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (×3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried (Na2SO4), filtered and evaporated to afford the title compound as a tan solid (86.3 g, 84%). LCMS (Method B): RT=3.76 min, M+H+=255/257. 1H NMR (400 MHz, CDCl3): 7.98 (d, J=2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 5.03 (s, 2H).