Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccccc1Oc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
AMR01059 A solution of 2-(2,4-dichlorophenoxy)benzoic acid (AMR01057, 200 mg, 0.706 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 406 mg, 2.12 mmol) and triethylamine (0.15 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and ethyl-4-amino-1-piperidine carboxylate (122 mg, 0.706 mmol) in dry DCM (4 mL) was added. After stirring at room temperature for 12 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel using DCM to DCM/MeOH 9:1 gradient as eluent gave 4-[2-(2,4-dichlorophenoxy)benzoylamino]piperidine-1-carboxylic acid ethyl ester (140 mg, 45%) as a white solid. Rf: 0.62 (DCM/MeOH 9:1) 1H NMR (300 MHz, CDCl3) 11.26 (3H, t, J=7.1 Hz, CH3), 1.40 (2H, m, CH2), 1.97 (2H, m, CH2), 3.00 (2H, m, CH2), 4.03 (2H, m, CH2), 4.13 (2H, q, J=7.1 Hz, CH3CH2O), 4.19 (1H, m, CH), 6.80 (1H, dd, J=8.2, 0.9 Hz, ArH), 6.90 (1H, d, J=8.8 Hz, ArH), 7.24 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.27 (1H, m, ArH), 7.36 (1H, br s, NH), 7.42 (1H, m, ArH), 7.53 (1H, d, J=2.5 Hz, ArH) and 8.19 (1H, dd, J=7.8, 1.8 Hz, ArH).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([CH3:10])([CH3:9])[C:6](=[O:8])[CH3:7]>C(OCC)C>[Br:1][CH2:7][C:6](=[O:8])[C:5]([O:4][CH3:3])([CH3:10])[CH3:9]
Reactant: COC(C)(C)C(C)=O
Reactant: BrBr
Solvent: CCOCC
Product: COC(C)(C)C(=O)CBr
Yield: 68.4 %

Procedure:
Bromine (26.42 g, 0.165 mole) was slowly added to a stirred solution of 19.2 g (0.165 mole) of 3-methoxy-3-methyl-2-butanone in 400 ml. diethyl ether at 15° C. After the addition was complete, the solvent was evaporated, and the residual orange oil distilled to give 22 g (68% yield) of 1-bromo-3-methoxy-3-methyl-2-butanone, b.p. 57°-59° C./1.7 mm. Hg.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([NH2:20])=[O:19])[NH:13]2)C1C=CC=CC=1.[H][H]>CO.[Pd].CCCCCC>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([NH2:20])=[O:19])[NH:13]2
Reactant: NC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Product: NC(=O)c1cc2c(O)cccc2[nH]1

Procedure:
4-(benzyloxy)indole-2-carboxamide (4.98 g) in 300 ml of methanol is stirred under 1 atm of hydrogen with 0.75 g of 10% palladium on carbon for 16 hr. The catalyst is filtered off through Celite filter aid, the filtrate concentrated, the residue taken up in ethyl acetate (300 ml) and filtered again. The clear filtrate is concentrated to 200 ml and hexane added to a volume of 450 mi. The cooled solution gives a small amount of gummy, dark material. The filtrate is diluted with hexane and cooled overnight to give a solid. Recrystallization from ethyl acetate/hexane then ethyl acetate gives 4-hydroxyindole-2-carboxamide, mp 219-221.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:14][CH3:15])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:14]([O:13][C@@H:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1)[CH3:15]
Reactant: CCO[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H]1CC[C@H](N)C1

Procedure:
A solution of cyclopent-3-enecarboxylic acid (2.25 g), diphenylphosphoryl azide (4.7 mL), and triethylamine (2.8 mL) in 25 mL toluene was refluxed for 7 h. The mixture was cooled to rt and treated with 10 mL of tert-butanol. The resulting mixture was refluxed for an additional 16 h. The solvents were evaporated and the crude residue was chromatographed with silica gel (1:10 ethyl acetate:hexanes) to give Cyclopent-3-enylcarbamic acid tert-butyl ester (racemic): (2.37 g). Borane-tetrahydrofuran (1.5 M in THF, 20 mL) was added dropwise to a solution of cyclopent-3-enylcarbamic acid tert-butyl ester (1.83 g) in tetrahydrofuran (30 mL) at 0° C. The solution was gradually warmed to rt and stirred for 16 h. The reaction solution was cooled to 0° C. and sodium hydroxide (1 N, 33 mL) was slowly added followed by 30% hydrogen peroxide (33 mL). The resulting mixture was stirred at rt for an additional 5 h and diluted with ethyl acetate (70 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated via rotary evaporator. Silica gel chromatography (1:1 ethyl acetate:hexanes) provided 0.25 g of cis-(3-hydroxycyclopentyl)carbamic acid tert-butyl ester (racemic) followed by 1.07 g of the trans isomer. A solution of cis-(3-hydroxycyclopentyl)-carbamic acid tert-butyl ester (201 mg) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 95 mg) at 0° C. After gas evolution had ceased, the mixture was stirred for 30 min at rt. Iodoethane (88 μL) was added to the mixture and the reaction was stirred at rt for 16 h. The excess sodium hydride was destroyed at 0° C. by the careful addition of aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and ammonium chloride and the organic layer was separated and washed with brine. The organic layer was dried over Na2SO4 and concentrated via rotary evaporator. Silica gel chromatography (1:4 ethyl acetate:hexanes) provided cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester (racemic) (102 mg). Cis-(3-ethoxycyclopentyl)carbamic acid tert-butyl ester was stirred in 1:1 trifluoroacetic acid:dichloromethane for 0.5 h. The solvent was removed by evaporation to provide cis-3-ethoxycyclopentylamine (racemic).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:9]Br)=[C:4]([CH2:7][Br:8])[CH2:5]Br.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:12]1([CH3:11])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:9][C:3]([CH2:2][Br:1])=[C:4]([CH2:7][Br:8])[CH2:5]2)(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: BrCC(CBr)=C(CBr)CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.7 %

Procedure:
19 g of tetrakis (bromomethyl)ethylene and 9 g of p-toluene sulfonamide were disolved in 220 ml of dimethylformamide. 30 g of anhydrous potassium carbonate was added and then stirred at room temperature for 20 hours. Thereafter solvent was removed by vacuum distillation. 50 ml of ethylacetate was added to obtain solid product, and solid product was purified by silica gel column chromatography. 12 g of the title compound was obtained (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=O)[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C1CCNC1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](C)C(=O)N1CCCC1

Procedure:
Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and pyrrolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.15 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using CHCl3/MeOH as the eluent.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:48]([NH:58][C@H:59]([C:65]([O:67]CC1C=CC=CC=1)=O)[CH2:60][CH2:61][C:62]([OH:64])=[O:63])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:48]([NH:58][C@H:59]([C:65]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:67])[CH2:60][CH2:61][C:62](=[O:63])[O:64][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-dodecanamide and N-carbobenzoxy-O-benzyl-L-glutamic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:40]([NH2:44])[CH2:41][CH2:42][CH3:43].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:27])[F:28])=[N:20][C:21]([C:22](=[O:24])[NH:44][CH2:40][CH2:41][CH2:42][CH3:43])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL of dichloromethane, followed by addition of butylamine hydrochloride (193 mg, 2.64 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (167 mg, 0.66 mmol) and triethylamine (100 mg, 0.99 mmol). The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-butylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 43a (120 mg, yield 60%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13](N)=[O:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([OH:14])=[O:1])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: NC(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1(c2ccc(Cl)cc2)CC1

Procedure:
In a mixed solvent consisting of 14 ml of dioxane and 29 ml of a 1N aqueous sodium hydroxide solution was suspended 1.4 g of 1-(4-chlorophenyl)cyclopropanecarboxamide [this compound can be obtained from 1-(4-chlorophenyl)cyclopropanecarboxylic acid produced according to the method described in Chem. Bet., 119, 3694 (1986)]. To the suspension was dropwise added 4.4 g of a 12% aqueous sodium hypochlorite solution at 5°-10° C. The suspension was subjected to reaction at 20°-25° C. for 1 hour. The reaction mixture was introduced into a mixed solvent consisting of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. To the thus treated organic layer was added the dioxane solution obtained in (1) above at 20°-25° C. The resulting mixture was subjected to reaction at the same temperature for 2 hours. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane/ethyl acetate=15/1) to obtain 0.37 g of N-[1-(4-chlorophenyl)cyclopropyl]-3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutanamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:15]2[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][N:3]=1>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:15]2[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH2:16]2)[C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC2(CC1)OCCO2
Solvent: C1COCCO1
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC(=O)CC1
Yield: 66 %

Procedure:
A stirred solution of methyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate (17 g, 42.5 mmol) in dioxane (450 mL, contains 1M HCl) was heated to reflux for 16 h. The bulk of solvent was then removed under reduced pressure, the crude material was neutralized with aq. NaHCO3, and extracted with ethyl acetate (300 mL×3). Organic layers were combined, dried over sodium sulfate, and evaporated to give the crude material, which was then purified by silica gel column chromatography to give the desired product (10 g). 1HNMR (300 MHz, CDCl3): δ 1.66 (d, J=6.9 Hz, 3H), 1.99-2.18 (m, 2H), 2.34-2.57 (m, 6H), 3.56-3.59 (m, 1H), 3.76 (s, 3H), 4.04 (q, J=6.9, 13.8 Hz, 1H), 8.70 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:11][C:12](=[O:33])[C@H:13]([CH2:31][OH:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:18][CH2:19][C:20](=[O:29])[NH:21]C(OC(C)(C)C)=O)[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>>[ClH:39].[CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH2:34][CH:35]([CH3:36])[CH3:37])[NH:11][C:12](=[O:33])[C@H:13]([CH2:31][OH:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:18][CH2:19][C:20](=[O:29])[NH2:21])[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCC(=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCC(N)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
N-(N′-(Boc)-glutaminyl-serinyl)leucine benzyl ester (715 g, 1.33 M) (prepared as described in Step 2) was suspended in iPAC (3.5 L) at room temperature. To the slurry was added a 3.8 M solution of HCl in iPAC (3.5 L, 13.3 M) whereupon all the solids dissolved. After a short time, the product crystallised. The mixture was stirred at room temperature for 3.75 hours when HPLC showed complete reaction. The slurry was diluted with iPAC (4.0 L), stirred for 1 hour at room temperature and the solid collected by filtration under nitrogen. The product is very hygroscopic in the presence of excess HCl and must be collected under dry nitrogen.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH3:18])[C:14]=1[N+:15]([O-:17])=[O:16])[CH:10]=O.[Cl-].[NH4+].[CH2:21]1C[O:24][CH2:23][CH2:22]1>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:21][CH2:22][CH2:23][OH:24])[CH:12]=[C:13]([CH3:18])[C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(C=O)cc(C)c1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: Cc1cc(C=CCCO)cc(C)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3-(hydroxypropyl)triphenylphosphonium bromide (10.5 g) in dry THF (100 ml) at 0°, under nitrogen was added n-butyllithium (1.8 M in hexane, 30 ml). The stirring was continued at 0° for 30 min then a solution of 3,5-dimethyl-4-nitrobenzaldehyde (4.5 g) in dry THF (50 ml) was added over 10 min. The mixture was stirred at -10° for 1 h and at 0° for 1 h, saturated ammonium chloride (50 ml) was added and the mixture was extracted with EA (3×50 ml) the organic extracts were washed with water, brine, dried, concentrated and purified by [FCS] (triethylamine deactivated silica) eluting with EA-methanol (9:1) gave the title compound (0.3 g). T.l.c. (Toluene:ethanol:0.88 ammonia solution 39:10:1) Rf 0.18.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[Na+].C(OCC)(=O)C>O>[Na+:25].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][S:21]([O-:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: CS(=O)(=O)OCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)([O-])Cc1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
5.80 g of methanesulfonic acid 3-benzyloxybenzyl ester and 5.21 g of sodium sulfite were dissolved in 50 ml of water and stirred at 90° C. for 5 hours. The mixture was allowed to cool to room temperature overnight, then 30 ml of ethyl acetate were added and the mixture was stirred in an ice bath for 1 hour. The precipitate was filtered off with suction, washed twice with 10 ml of ice-water and twice with 10 ml of ice-cold ethyl acetate, and dried in a vacuum drying cabinet at 40° C. overnight. This gave the product (2.37 g) with a molecular weight of 300.3 g/mol (C14H13O4S.Na); MS (ESI): m/e=296 (M−Na++H2O+H+).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:8])[CH:5]([Cl:7])[CH3:6].C(N(CC)CC)C.[CH3:16][N:17]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:18](Cl)=[O:19]>C1C=CC=CC=1>[Cl:7][CH:5]([CH3:6])[C:4]([O:8][C:18](=[O:19])[N:17]([CH3:16])[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:3][O:2][CH3:1]
Reactant: CN(C(=O)Cl)C1CCCCC1
Reactant: CONC(=O)C(C)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CON=C(OC(=O)N(C)C1CCCCC1)C(C)Cl
Temperature: 25 °C

Procedure:
N-Methoxy-α-chloropropionamide (13.8 grams; 0.1 mole), benzene (70 ml) and triethylamine (12 grams; 0.12 mole) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. N-Methyl-N-cyclohexylcarbamoyl chloride (17.9 grams; 0.1 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-1-methyl-2-(N-methyl-N-cyclohexylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH2:12].C1COCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][CH3:11])=[O:6]
Reactant: CN
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1cccc(I)c1
Reaction time: 8 h
Yield: 26 %

Procedure:
To a cooled (0° C.) solution of 3-iodobenzoyl chloride (2.66 g; 10.0 mmol) in DCM (10 mL) was slowly added a 2 M solution of methylamine in THF (10 mL, 2.0 eq.). Upon completion of the addition, the ice bath was removed and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was treated with aq. NaHCO3 (25 mL) and subsequently extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel to give the desired 3-iodo-N-methylbenzamide (0.67 g, 26% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([CH:30]2[CH2:35][CH:34]3[CH2:36][CH:31]2[CH2:32][CH2:33]3)[CH:29]=1)=O)C.[CH2:38]([NH2:40])[CH3:39]>CO>[CH2:38]([NH:40][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([CH:30]2[CH2:35][CH:34]3[CH2:36][CH:31]2[CH2:32][CH2:33]3)[CH:29]=1)=[O:3])[CH3:39]
Reactant: CCOC(=O)c1cn(C2CC3CCC2C3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cn(C2CC3CCC2C3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.7 mg, 0.11 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 3.7 of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.62 (s, 1H), 9.26 (s, 1H), 8.90 (s, 1H), 7.54 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.9 Hz), 4.85-4.88 (m, 1H), 3.26-3.64 (m, 9H), 2.91-2.94 (m, 2H), 2.82 (s, 3H), 2.55 (s, 1H), 2.44 (s, 1H), 2.03 (br s, 8H), 1.59-1.61 (m, 4H), 1.35-1.41 (m, 2H), 1.19 (t, 1H, J=7.3 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H35N7O2: 501.29, Found: 502.3 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].[NH3:29]>C(O)C.C(Cl)(Cl)Cl>[NH2:29][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: N
Reactant: COc1cc2c3c(c1)c(Cl)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc2c3c(c1)c(N)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-7-chloro-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1 g), ammonia in ethanol (13 ml) and chloroform (20 ml) was heated at 100° C. in a sealed tube for 4 days. The solvent was evaporated and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (20:1) to give crystals of 2,3-dihydro-7-amino-9-methoxy-6-(1-indolinyl-carbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.35