Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[CH2:29]([NH:31][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH3:30]
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Reactant: CCN
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 3.2 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Ethylamine (0.021 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further ethylamine (0.021 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, ethylamine (0.021 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time ethylamine (0.021 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. Finally, additional ethylamine (0.021 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 170° C. for 1 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was re-purified by Mass Directed Automated Preparative HPLC (Method E, using Waters Atlantis column 100 mm×19 mm, 5 um). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (3.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl.O>[CH:16]1([CH2:15][C@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[C:12]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[O:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1ccccn1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.64 mmol), in methylene chloride (10 mL) was treated with oxalyl chloride (0.07 mL, 0.64 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.34 mL, 1.92 mmol) and commercially available 2-amino-pyridine (68 mg, 0.64 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-N-pyridin-2-yl-propionamide (42 mg, 17.4%), as a white solid. 1H NMR (DMSO-d6) δ: 10.85 (s, 1H), 8.33 (d, J=3.9 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 7.12 (t, J=5.9 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.08 (br. s., 1H), 4.39 (d, J=18.6 Hz, 1H), 4.03 (d, J=19.1 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 1.49-1.88 (m, 7H), 0.85-1.32 (m, 6H).
Reaction SMILES: [Li+].[BH4-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](OCC)=[O:13])=[CH:7][C:6]=1[O:17][CH3:18])#[N:4].O>C1COCC1>[OH:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[C:6]([O:17][CH3:18])[CH:7]=1
Reactant: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCO)ccc1C#N
Reaction time: 12 h

Procedure:
LiBH4 (1.7 mL, 3.4 mmol, 2 M in THF) was added to a stirred solution of ethyl (4-cyano-3-methoxyphenyl)acetate (0.50 g, 2.4 mmol) in THF (25 mL) at 0° C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3→1:1) to give 4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H NMR (500 MHz, CDCl3) δ 7.52 (d, 1H, J=7.0 Hz), 6.91 (d, 1H, J=7.8 Hz), 6.88 (s, 1H), 3.95 (s, 3H), 3.92 (t, 2H, J=6.4 Hz), 2.93 (t, 2H, J=6.4 Hz); LCMS: [(M+1)]+=178.3; tR=2.1 min.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH:14]1[C:19](=[O:20])[C:18]([OH:21])=[CH:17][O:16][C:15]=1[CH2:22]Cl>>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:22][C:15]1[O:16][CH:17]=[C:18]([OH:21])[C:19](=[O:20])[CH:14]=1)=[O:5]
Reactant: O=c1cc(CCl)occ1O
Reactant: O=C(O)c1cccc(O)c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1cc(=O)c(O)co1)c1cccc(O)c1O
Yield: 44.2 %

Procedure:
By following the procedure of Example 1 by employing 1.0 g(6.5 mmole) of 2,3-dihydroxybenzoic acid, 0.26 g (8.5 mmole) of sodium hydroxide and 0.92 g(7.6 mmole) of chlorokojic acid, there was obtained 0.8 g(50.2%) of 2-(2,3-dihydroxybenzoyl)oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]([CH:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:15][CH2:14][CH2:13]3)O)[CH:7]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:29])=[C:6]([CH:7]=1)[CH2:8][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:15][CH2:14][CH2:13]2
Reactant: COc1ccc(CN2CCCc3cc(C(O)c4cc(Br)ccc4Cl)ccc32)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(CN2CCCc3cc(Cc4cc(Br)ccc4Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To an ice cold solution of (5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-methanol (2.2 g, 4.7 mmol) in dichloromethane (50 mL) was added Et3SiH (3.7 mL, 23.3 mmol) followed by BF3.OEt2 (1.5 mL, 11.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of aq. NaHCO3. The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with dichloromethane (2×50 mL), washed with brine (10 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 6-(5-Bromo-2-chloro-benzyl)-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (1.48 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:24][CH2:22][CH3:23])[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCNc1cc(Cl)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 80 °C
Yield: 76.6 %

Procedure:
A suspension of 5A (80 mg, 0.245 mmol), ethanamine (0.6 mL, 1.200 mmol, 2 M/THF) and DIEA (0.086 mL, 0.491 mmol) in NMP (0.7 mL) was heated at 80° C. for 5 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration and washed with a small amount of DCM to give 6-chloro-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as a yellow solid 62.8 mg. HPLC Rt=2.517 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H]=335.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12]>[Pd].O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)NS(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1C(=O)NS(C)(=O)=O
Yield: 79.3 %

Procedure:
In the same way as that described in Example 11, Step 2, using 2-methyl-1-(methylsulphonylaminocarbonyl)-5-nitrobenzene (3 g, 11.6 mmol), 10% palladium on carbon (0.3 g, 10% (w/w)) in water (2 ml) and ethanol (100 ml), the title compound (2.1 g, 79%) was afforded as a pale yellow crystalline solid. mp 174°-176° C. 1H NMR (360 MHz, D6-DMSO) δ 2.17 (3H, s), 3.32 (3H, s), 6.61 (1H, dd, J=8.1 and 2.5 Hz), 6.67 (1H, d, J=2.4 Hz), 6.92 (1H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1]C1C=C2C(C(=O)C(C(O)=O)=CN2C2C=CC=CC=2)=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36](C4C=CN=CC=4)[CH:37]=3)[C:32](=[O:45])[C:31]([C:46]([NH2:48])=[O:47])=[CH:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:36]1[CH:37]=[C:38]2[C:33]([C:32](=[O:45])[C:31]([C:46]([NH2:48])=[O:47])=[CH:30][N:29]2[C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:34][CH:35]=1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Reactant: O=C(O)c1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O

Procedure:
7-Chloro-1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxamide [IV; R=H, R1 =C6H5, R2 =H, R6 =H, X=Cl]was prepared from 3.60 g 7-chloro-1,4-dihydro-4-oxo-1-phenyl3-quinolinecarboxylic acid by the procedure of Example 1, part (h), and was obtained (3.00 g) in the form of a colorless solid, m.p. 297-299° C. when recrystallized from DMF.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]3[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=3[CH:11]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Product: CC(=O)c1cc2c(cc1OCc1ccc(C)cc1)C(C)(C)CCC2(C)C
Yield: 131.4 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone (0.116 g, 0.471 mmol) was alkylated with 4-methylbenzylchloride (0.93 g, 0.659 mmol, 0.087 mL) as described in Example 21. Aqueous workup gave 1-[3(4-Methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl]ethanone 0.217 g (131% crude) as a pale orange solid: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, ArH), 7.33 and 7.20 (d, of ABq, J=7.8 Hz, 4H, Ar-H), 6.91 (s, 1H, ArH), 5.08 (s, 2H, OCH2), 2.56 (s, 3H, CH3), 2.35 (s, 3H, ArCH3), 1.66 (br s, 4H, 2CH2), 1.28 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C:50]1(C)[CH2:55][CH2:54]N(C2N3C=C(C4C=C(C5C=C(C)C=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)[CH2:52][CH2:51]1)C=C>>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=5[O:33][C@H:55]([CH2:50][CH:51]=[CH2:52])[CH3:54])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cccc(F)c5O)c4)cn23)CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cccc(F)c5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 70 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-fluoro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate in 70% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-7-methyl-2-(5′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)imidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 684.20.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1>C1COCC1.O>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: CC#CC(=O)O
Reactant: Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
Dissolved 597 mg (7.10 mmol) 2-butynoic acid in 25 ml THF under N2 and chilled to 0° C. Added 950 μl (7.30 mmol) isobutyl chloroformate and 780 μl (7.10 mmol) N-methylmorpholine and stirred for 10 minutes. Added dropwise a solution of 778 mg (2.84 mmol 6-amino-4-[(3-methylphenyl)amino]-3-quinolinecarbonitrile, stirred for 15 minutes at 0° C. and then at 25° C. overnight. Stripped solvent and slurried residue with water, drying the gummy solid in vacuo briefly. Boiled solid in ethyl acetate and collected. Recrystallized from DMF, using ethanol to crash out the product, and dried in vacuo, giving 401 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=341.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[C:13]([O:31][CH3:32])=[C:14]([C:19]([CH3:30])([CH3:29])[CH2:20][C:21]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH2:22][OH:23])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C>ClCCl.O>[F:11][C:12]1[C:13]([O:31][CH3:32])=[C:14]([C:19]([CH3:30])([CH3:29])[CH2:20][C:21]([OH:24])([C:25]([F:28])([F:27])[F:26])[CH:22]=[O:23])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: COc1c(C(C)(C)CC(O)(CO)C(F)(F)F)ccc(C)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)(C)CC(O)(C=O)C(F)(F)F)ccc(C)c1F
Temperature: -78 °C
Yield: 76.9 %

Procedure:
1.57 g (12.31 mmol) of oxalyl chloride is introduced into 27 ml of dichloromethane and cooled to −78° C. After dropwise addition of 1.93 g of DMSO, dissolved in 5.2 ml of dichloromethane, the batch is stirred for five more minutes. Then, 3.65 (11.26 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol, dissolved in 11.5 milliliters of dichloromethane, is added in drops. After two hours of stirring, the batch is carefully mixed with 6.61 ml (56.28 mmol) of triethylamine. After one and one-half hours of vigorous stirring at room temperature, water is added, and the batch is shaken twice with dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, saturated sodium bicarbonate solution and brine. After the organic phase is dried, the solvent is spun off. 2.79 g (76.9%) of the aldehyde that is obtained, which is further incorporated in crude form, remains.
Reaction SMILES: [C:1](=[O:4])([O-:3])[NH2:2].[NH4+:5].[NH2:6][C:7]([NH2:9])=[O:8].N.C(=O)=[O:12].C(=O)([O-])[NH2:15]>>[NH2:6][C:7]([NH2:9])=[O:8].[NH3:2].[C:1](=[O:4])([O-:12])[O-:3].[NH4+:15].[NH4+:5]
Reactant: O=C=O
Reactant: NC(=O)[O-]
Agent: N
Agent: NC(N)=O
Agent: [NH4+]
Product: O=C([O-])[O-]

Procedure:
In a method for the concurrent production of ammonia and urea comprising the steps of producing ammonia in an ammonia-synthesis apparatus, absorbing ammonia at the exit of the ammonia-synthesis reactor with water, thus obtaining a concentrated aqueous solution of ammonia, utilizing the concentrated solution of ammonia for the absorption of the CO2 contained in the raw gases for the synthesis of ammonia, obtaining ammonium carbamate, converting the ammonium carbamate partially into urea in a urea-synthesis reactor, thermally decomposing the carbamate which has not been converted into urea and stripping the decomposition products with a gas selected from the group consisting of ammonia, CO2 and inerts, discharging from the stripping zone a solution of urea which still contains carbamate, recycling the products of decomposition of the carbamate to the urea-synthesis reactor, distilling under a pressure of from 3 to 30 atm, in at least one stage, the solution of urea to obtain liquid ammonia and one or more ammoniacal solutions of ammonium carbonate, and an aqueous solution of urea deprived of ammonium carbamate the improvement which comprises introducing the CO2 -containing gas at the bottom, or near the bottom, of an absorber which is split into two sections, the lower section being a film-absorber and the upper section being a plate-absorber, the absorbing solution in the upper section being the concentrated aqueous solution of ammonia aforesaid, the absorbing solution in the lower section being one or more of the aqueous ammoniacal solutions of ammonium carbonate as obtained by distillation of the solution of urea under a pressure of from 3 to 30 atm. with addition of liquid ammonia.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[CH2:9]([S:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SC1=NCCS1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CSC2=NCCS2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 258.8 %

Procedure:
To a dry, nitrogen (N2)-purged 500 milliliter (mL) round bottom flask was added 1.15 grams (g) (4.8 mmol) sodium hydride. To this was added 150 mL dry tetrahydrofuran and 5.70 g (4.8 mmol) 2-mercaptothiazoline in 24 mL tetrahydrofuran. After approximately 15 minutes of stirring at room temperature, 5.5 mL (4.8 mmol) benzyl chloride was added and stirred for an additional 5 minutes. Tetrahydrofuran was removed by rotary evaporation and product was dissolved in hexane. After filtration, the product was recrystallized from hexane to yield 2.6 g of white crystals (26% yield). 1H NMR (CDCl3): 3.434 ppm, t, 2H; 4.259 ppm, t, 2H; 4.413 ppm, s, 2H; 7.317 ppm, m, 5H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:16]([CH3:19])([O-])=O.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:15][C:12](/[CH:13]=[CH:19]/[NH2:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N/C=C/c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 80 °C
Yield: 92.5 %

Procedure:
To a stirred solution of 5-(3,4-dichlorophenyl)furfural (1.18 g, 4.89 mmol) in acetic acid (30 ml) was added nitromethane (0.535 ml, 9.78 mmol) and ammonium acetate (1.13 g, 14.7 mmol). The reaction mixture was heated at 80° C. for 4.5 h. Cooled reaction mixture was poured onto ice water (30 ml) and thus formed precipitate was filtered, washed with water and dried under vacuum to give 1.15 g (83%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.37 (d, 1H), 7.43 (d, 1H), 7.76 (d, 1H), 7.95 (dd, 1H), 8.03 (d, 1H), 8.19 (d, 1H), 8.31 (d, 1H).
Reaction SMILES: C[O-:2].[Na+].[Na].NO.Cl.C[N:9](C)[CH:10]=[N:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19]>CO.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][CH:10]=[N:9][OH:2])=[C:13]([CH3:19])[CH:14]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)ccc1N=CN(C)C
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(Cl)ccc1NC=NO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a sodium methoxide solution prepared by dissolving 19 grams of sodium metal in 250 milliliters of methanol was added 56 grams of hydroxylamine:hydrochloride in 300 milliliters of methanol. To the resulting mixture was added 98 grams (0.5 mole) of N,N-dimethyl-N'-(4-chloro-2-methylphenyl)methanimidamide. The mixture was stirred at room temperature for 18 hours. The solid reaction product was recovered by filtration and the filtrate concentrated by evaporation under reduced pressure. The residue and the solid reaction product (filter cake) were suspended in water, collected by filtration, water washed and recrystallized from ethanol. The N-(4-chloro-2-methylphenyl)-N'-hydroxymethanimidamide product was recovered in a yield of 81.7 grams (89% of theoretical) and melted at 171°-171.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[CH2:22][CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C.CCOC(C)=O.CCCCCC>Br>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[CH2:22][CH3:23])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(OC)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Ethyl-4-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester is refluxed in 48% HBr for 2 hours. After concentration, the residue is dissolved in DCM and (Boc)2O (1.5 eq) and triethylamine (4 eq) are added. The resulting mixture is stirred at room temperature for 30 minutes. After aqueous workup, flash column chromatography (30% EtOAc/hexane) gave 4-(2-Ethyl-4-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: (ES+): 307.2 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][CH2:4]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.C1COCC1.C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[C:23]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:5][CH2:4]1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCCN1CCC(CN)CC1
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN1CCC(CNC(=O)c2cc(F)cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-(4-(aminomethyl)piperidin-1-yl)ethylcarbamate (50 mg, 0.19 mmol), TEA (135 μL, 0.972 mmol), and 3-fluoro-5-(trifluoromethyl)benzoic acid (48 mg, 0.23 mmol) in a mixture of 1:1 CH2Cl2:THF (2 mL) was treated with a solution of HATU (111 mg, 0.292 mmol) in DMF (1 mL). The resulting solution was stirred overnight, then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously and allowed to separate for 15 minutes. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs.