Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([C:28]2C=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6](=O)[CH:5]=[C:4]([C:8](=NOC(NCCCCCCCC)=O)[C:9]2C=CC=C[CH:10]=2)O1.[CH:34]1([C:40]2([CH3:66])[C:44](=[O:45])[CH:43]=[C:42]([C:46](=[N:53][O:54][C:55]([NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]CC)=[O:56])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:41]2)CCCCC1.ClC1C=CC(C2(C)C(=O)C=C(C(=NOC(NCCCCCCCC)=O)C3C=CC=CC=3)O2)=CC=1.CC(C1C=CC(C2(C)C(=O)C=C(C(=NOC(NCCCCCCCC)=O)C3C=CC=CC=3)O2)=CC=1)(C)C>>[CH3:66][C:40]1([CH3:34])[C:44](=[O:45])[CH:43]=[C:42]([C:46](=[N:53][O:54][C:55]([NH:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:32][CH2:31]/[CH:30]=[CH:29]/[CH2:28]/[CH:2]=[CH:6]/[CH2:5][CH2:4][CH2:8][CH2:9][CH3:10])=[O:56])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:41]1
Reactant: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(c2ccccc2)O1)c1ccccc1
Reactant: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(C2CCCCC2)O1)c1ccccc1
Agent: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(c2ccc(C(C)(C)C)cc2)O1)c1ccccc1
Agent: CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(c2ccc(Cl)cc2)O1)c1ccccc1
Product: CCCCC/C=C/C/C=C/CCCCCCCCNC(=O)ON=C(C1=CC(=O)C(C)(C)O1)c1ccccc1

Procedure:
2-cyclohexyl-2-methyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone 2-methyl-2-phenyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone; 2-(4-chlorophenyl)-2-methyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone; 2-[4-(1,1-dimethylethyl)phenyl]-2-methyl-5-[[[[(octylamino)carbonyl]oxy]imino]phenylmethyl]-3(2H)-furanone;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH2:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])=[CH:6][C:5]=1[C:13]([F:14])([F:16])[F:15]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cc(OC)c(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC)c(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a stirred solution of 5-methoxy-4-amino-2-trifluoromethyl-benzoic acid methyl ester (552 mg, 2.22 mmol) in 6.6 mL CH2Cl2 at 0° C. under nitrogen was added pyridine (180 μL, 2.22 mmol) followed p-nitrophenyl chloroformate (448 mg, 2.22 mmol) as a solid. After stirring for 1 hour, the reaction was diluted to 30 mL with CH2Cl2 and washed 2×30 mL with 2N HCl and 1×30 mL with H2O. The organics were dried (MgSO4), filtered and concentrated to the p-nitrophenyl carbamate which was isolated as a white foam (878 mg, 96%). 1H-NMR (400 MHz, CDCl3) δ 8.57 (br s, 1H), 8.30 (d, 2H), 7.77 (br s, 1H), 7.40 (d, 2H), 7.37 (s, 1H), 4.03 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([NH2:20])[CH2:16]1)[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C@@H:17]2[CH2:18][CH2:19][N:15]([CH2:13][CH3:14])[CH2:16]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CCN1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CC[C@@H](NC(=O)c2ccc(N)c(OC)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 424 mg, 2.54 mmol) and (3R)-1-ethylpyrrolidin-3-amine (Intermediate 246; 312 mg, 2.73 mmol) in DMF (10 mL) was added DIPEA (1.4 ml, 8.04 mmol). The resultant solution was treated with HATU (1.21 g, 3.18 mmol) and stirred, under nitrogen, at ambient temperature overnight.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]2[CH:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:3]12.S(Cl)([Cl:21])=O>>[Cl:21][C:16]([C:14]1[CH:15]=[C:3]2[N:4]([CH:13]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:2]2=[O:1])=[O:18]
Reactant: O=C(O)c1cc2n(c1)CCc1ccccc1C2=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2n(c1)CCc1ccccc1C2=O
Yield: 89 %

Procedure:
6,11-Dihydro-11-oxo-pyrrolo[2,1-b][3]benzazepine-2-carboxylic acid (24 g., 99 mmoles) in 100 ml. of thionyl chloride was refluxed for 15 minutes. The volatiles were removed under vacuum and the residue was triturated in ether. Filtration and air-drying yielded 2-chlorocarbonyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one (23 g., 89%), m.p. 147°-148.5°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH2:49]([O:48][CH2:47][CH2:46][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: BrCCCOCc1ccccc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and benzyl 3-bromopropyl ether to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′43-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (89%) as a colorless solid: mp 112-113° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 6H), 7.14 (d, J=6.0 Hz, 1H), 7.06-6.95 (m, 2H), 6.41-6.39 (m, 2H), 4.63 (AB, 2H), 4.54-4.48 (m, 4H), 3.94-3.80 (m, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.95 (t, J=9.0 Hz, 2H), 2.07-1.99 (m, 2H); MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[F:22][C:23]1([F:33])[O:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([NH2:32])[C:25]=2[O:24]1>>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:32][C:31]4[C:25]5[O:24][C:23]([F:33])([F:22])[O:27][C:26]=5[CH:28]=[CH:29][CH:30]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cccc4c3OC(F)(F)O4)ncc21

Procedure:
The title compound was synthesized from 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one and 2,2-difluorobenzo[d][1,3]dioxol-4-amine using the procedure described in the general Buchwald Reaction Scheme. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.84 (m, 9 H) 3.97 (t, J=14.40 Hz, 2 H) 4.50-4.70 (m, 1 H) 7.14 (d, J=2.27 Hz, 1 H) 7.31 (dd, J=7.45, 2.15 Hz, 1 H) 8.21 (s, 1 H) 9.39 (s, 1 H). [M+H] calculated for C20H19F4N5O3, 454; found 454.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:19])=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1CBr
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of 2-(4-Methoxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.41 g, 5.09 mmol), N-bromosuccinimide (951 mg, 5.34 mmol) and benzoyl peroxide (62 mg, 0.25 mmol) in carbon tetrachloride (20 mL) was refluxed for 15 h before it was cooled to room temperature and partitioned between dichloromethane and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (1.71 g): MS: (+) m/z 355.96, 357.96 (M+1, 79Br/81Br).
Reaction SMILES: CC(C)([O-])C.[K+].C[C:8]1(O)C=C[CH:11]=[N:10][CH2:9]1.CI.O.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:20][O:21][C:22]1[CH:18]=[CH:19][C:9]([CH3:8])=[N:10][CH:11]=1
Reactant: CC1(O)C=CC=NC1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Potassium tert-butoxide (5.4 g, 48 mmol) was added to 3-methyl-pyridin-3-ol (5 g, 45.87 mmol) in THF (200 mL) at 0° C. The mixture was stirred at room temperature for 30 min. MeI (3.2 mL, 48 mmol) was added dropwise at 0° C. and stirring was continued at room temperature for 8 h. Water was added and the mixture was evaporated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography to give 5-methoxy-2-methyl-pyridine (4.8 g, 85%).
Reaction SMILES: [CH:1]1[C:6]([CH2:7]Cl)=[CH:5][CH:4]=[C:3]([Cl:9])[CH:2]=1.[CH3:10][NH:11][CH3:12]>O1CCCC1.C(OCC)C>[CH3:10][N:11]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([Cl:9])=[CH:2][CH:1]=1)[CH3:12]
Reactant: CNC
Reactant: ClCc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The solution of 141 g of α,p-dichlorotoluene in 200 ml of tetrahydrofuran is added dropwise to an ice-cold saturated solution of dimethylamine in 1 liter of tetrahydrofuran and the mixture stirred for 2 days at 25°. It is diluted with diethyl ether, washed with 2N aqueous sodium hydroxide, the organic layer dried, evaporated, the residue distilled and the fraction boiling at 106°/12 mm Hg collected, to yield the N,N-dimethyl-4-chlorobenzylamine.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:35][CH:34]=1>C1COCC1>[Si:41]([O:40][CH2:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])=[CH:38][CH:37]=1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CBr)cc1
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CC(C#N)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of phenylacetonitrile (1.5 mL, 12.7 mmol) in THF (40 mL) containing HMPA (11 mL, 63.4 mmol) was cooled to -78° C. and treated with 16 mL (16 mmol) of a 1.0M THF solution of lithium bis(trimethylsilyl)amide dropwise while the temperature was maintained at -78° C. The reaction was stirred at -78° C. for 1.5 hours, and a solution of the product of Step B (2.00 g, 6.34 mmol) in THF (8 mL) was added dropwise with the temperature maintained below -70° C. The reaction temperature was maintained below -68° C. for 3 hours. The reaction was quenched at this temperature by addition of 1N NaHSO4. After warming to room temperature, the mixture was partitioned between EtOAc and water, and the combined organic layers were washed with water, saturated NaHCO3, brine, dried (MgSO4), filtered, then concentrated in vacuo. The residue was chromatographed on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.5 g (67%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[CH2:25]([Li])CCC.CI>C1COCC1>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([CH3:25])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Reactant: [Li]CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of 30 g of 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-chloro-4-fluorobenzoic acid in 800 mL of anhydrous THF was stirred with a mechanical stirrer and treated with 3.36 g of 80% NaH. The stirred mixture was kept under a nitrogen atmosphere and heated to 60° C. for one hour. After formation of the sodium carboxylate salt, the mixture was cooled to -110° C. and 32.3 mL of 2.5M n-butyllithium in hexanes was added never allowing the temperature to exceed -100° C. The reaction was stirred at -110° C. for ten minutes, subsequently treated with 9.3 mL of methyl iodide and allowed to warm to room temperature. The mixture was quenched with 3N HCl and the volatiles removed. A precipitate formed which was collected and recrystallized from ethanol/water to give 24.5 g of a white solid: mp 155.0° C.; 1HNMR (CDCl3) δ 2.06 (m, 3H), 4.01 (s, 3H), 7.27 (d, 1H, J=9.6 Hz), 8.17 (d, 1H, J=7.6 Hz). Anal. Calcd for C13H9O2Cl1N2F4 : C, 46.38; H, 2.69; N, 8.32. Found: C, 46.46; H, 2.65; N, 8.33.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([CH2:14][O:15]CC1C=CC=CC=1)([OH:13])[CH2:4][O:5]CC1C=CC=CC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:24])([F:23])[C:3]([OH:13])([CH2:14][OH:15])[CH2:4][OH:5]
Reactant: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Product: OCC(O)(CO)C(F)(F)F
Reaction time: 8 h
Yield: 104.3 %

Procedure:
A solution of 1,1,1-trifluoro-3-[(benzyl)oxy]-2-{[(benzyl)oxy]methyl}-2-propanol (98.9 g, 290.9 mmol) in ethanol (1750 ml) was added to 5% palladium on carbon (9.73 g, wet, Degussa, E101 No/W) under nitrogen. The mixture was then stirred under an atmosphere of hydrogen using a Wright valve in a 5 liter hydrogenation vessel. After approximately 3 hours most of the theoretical volume of hydrogen had been taken up. After stirring under hydrogen overnight (approximately a further 1 liter of hydrogen had been taken up overnight), the catalyst was filtered off through a pad of celite and the pad washed with ethanol. The filtrate and washings were then concentrated under reduced pressure and the residue azeotroped (×2) with dichloromethane whereupon the residue became solid. This material was left on the vacuum pump to give the title compound (48.56 g) as an off white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.[O:24]1[CH2:29][CH2:28]O[CH2:26][CH2:25]1.O1C=CC=C1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[O:24]1[CH:29]=[CH:28][CH:26]=[C:25]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(Oc1ccc(-c2cc3nccnc3[nH]2)cc1)C(F)(F)F
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccco1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1coc(-c2ccc(-c3cc4nccnc4[nH]3)cc2)c1
Temperature: 180 °C

Procedure:
A mixture of 6-(4-trifluoromethanesulfonyloxyphenyl)-5H-pyrrolo[2,3-b]pyrazine [20 mg, Reference Example 18(e)], dioxane (2.5 mL), furan-2-boronic acid (9.8 mg), sodium carbonate solution (0.06 mL, 2N), and tetrakis(triphenylphosphine)palladium[0] (4 mg) was heated at 180° C. in a microwave oven for 40 minutes. The reaction mixture was then evaporated and the residue was subjected to chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give, after trituration with a mixture of ethyl acetate and methanol, the title compound (7 mg) as a yellow solid. MS: 262.1 (MH+). RT=3.05 minutes.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH3:9].[N:10]1[CH2:11][CH2:12][CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16](=[O:23])[C:15]=12.[Cl-].[NH4+]>BrCCCCOCC.CCOCC.ClCCCl>[OH:23][C:16]1([CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH3:9])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[N:14]2[CH2:13][CH2:12][CH2:11][N:10]=[C:15]12
Reactant: O=C1C2=NCCCN2c2ccccc21
Reactant: CCOCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCCl
Product: CCOCCCCC1(O)C2=NCCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ether (10 ml) and a few drops 4-bromo-1-ethoxybutane were added to magnesium turnings (1.46 g). After the reaction started, the remainder of the 4-bromo-1-ethoxybutane (total 10.86 g) in ether (50 ml) was added dropwise over 20 minutes. The mixture was stirred under argon at room temperature for 30 minutes, cooled to 0° C. over 30 minutes and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° C. for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml), and the mixture stirred for a further 20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound as the free base (2.99 g), m.p. 123°-124° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 189°-190° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:20].[Na+]>CO>[NH2:20][CH:10]1[CH:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][N:2]([CH3:1])[CH2:11]1
Reactant: CN1CC(=O)c2ccccc2C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CN1CC2=CC=CCC2C(N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.5 %

Procedure:
According to Scheme 23, a mixture of 2-methyl-2,3-dihydro-4-(1H)-isoquinolone (630 mg, 3.9 mmol, Nichols, D. E. et al.; WO9706799), ammonium acetate (3.0 g, 39 mmol) and NaCNBH3 (491 mg, 7.8 mmol) in 25 mL of dry methanol was stirred for 2 days at RT. The solvent was removed and the residue was acidified to pH 2 to destroy the excess NaCNBH3. After basification with aq Na2CO3 to pH 10, the product was extracted into ether. The ether layer was dried (K2CO3) and the solvent was evaporated to provide 330 mg of the racemic 4-amino-2-methyltetrahydroisoquinoline. 1H NMR (CDCl3): δ 2.20 (bs, 2H, NH2), δ 2.60 (s, 3H, NCH3), δ 2.90 (d, 2H, CHCH2N), δ 3.55 (d, 1H, ArCH2N), δ 3.90 (d, 1H, ArCH2N), δ 4.15 (t, 1H, ArCHN), δ 7.20-7.60 (m, 4H, ArH).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]([O:11][CH:12](Cl)[CH3:13])=[O:10].[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O-:37])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17].[Na+]>>[OH:15][C@@H:16]([C@H:18]1[C:38](=[O:39])[N:20]2[C:21]([C:35]([O:37][CH:12]([O:11][C:9]([N:3]3[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]3[CH3:8])=[O:10])[CH3:13])=[O:36])=[C:22]([S:25]/[CH:26]=[CH:27]\[C:28]3[S:32][CH:31]=[N:30][C:29]=3[CH2:33][OH:34])[C@H:23]([CH3:24])[C@H:19]12)[CH3:17]
Reactant: CC(Cl)OC(=O)N1[C@H](C)CCC[C@@H]1C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)OC(=O)N1[C@H](C)CCC[C@@H]1C
Yield: 17.3 %

Procedure:
In the same manner as in step b) in Example 125, 98 mg of the title compound was prepared from 283 mg of 1-[(cis-2,6-dimethylpiperidin-1-yl)carbonyloxy]ethyl chloride and 404 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18].Cl[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCN(CC)CCCl
Reactant: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)O)cn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)OCCN(CC)CC)cn2c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.6 g) was reacted with 1-chloro-2-(diethylamino)ethane (2.7 g) and anhydrous K2CO3 (2.8 g) in dimethylformamide (40 ml) under stirring at 50° C. for 8 hours. After dilution with water, the precipitate was filtered off and washed with water until neutral: crystallization from isopropyl ether gave 2.1 g of 2-trans-[2-(2-methylphenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, 2-diethylamino-ethyl ester. By proceeding analogously, the following compounds were prepared:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[NH2:19])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[NH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH2:3][C:2](=[O:22])[NH:1]4)[CH:11]=2)[NH:15][N:14]=1
Reactant: Nc1n[nH]c2ccc(-c3cccc4[nH]ccc34)cc12
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Nc1n[nH]c2ccc(-c3cccc4c3CC(=O)N4)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To the suspension of 5-(1H-indol-4-yl)-1H-indazol-3-ylamine (0.82 g, 3.33 mmol) in t-BuOH:ethanol:acetic acid (20.5 mL:12 mL:6 mL) was added pyridinium tribromide (3.17 g, 9.9 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, it immediately became a dark pink color. Zinc dust (excess) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and the solvent was removed under reduced pressure. The residue was washed with ample of water. The solid was triturated with DCM to give 0.563 g (77%) of 4-(3amino-1H-indazol-5-yl)-1,3-dihydro-indol-2-one.
Reaction SMILES: OCCNS([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])(=O)=O.ClC1C=CC([NH2:22])=CC=1C1C=CC=CN=1>>[C:11]([NH2:22])(=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:8][CH:9]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1cccc(S(=O)(=O)NCCO)c1
Product: NC(=O)c1ccccc1

Procedure:
Procedure G was used to couple 3-(2-hydroxyethylsulfamoyl)benzoic acid with 4-chloro-3-(pyridin-2-yl)aniline (42 mg) to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-[(2-hydroxyethyl)amino]sulfonyl]-benzamide. MS (Q1) 432.0 (M)+.