Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 37897.4 %

Procedure:
3-Methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c (53 mg, 0.174 mmol) and 5-chloro-1,3-dihydro-indol-2-one (29 g, 0.84 mmol) was dissolved in 0.9 ml of ethanol under stirring, and added with piperidine (0.1 ml, 1.0 mmol) to the solution at room temperature. The mixture was heated to reflux for 2 hours in an oil bath and lots of precipitates were formed. Then the ice-salt bath was removed, and the reaction mixture was naturally cooled down to room temperature, filtered to obtain the title compound (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 10 (30 g, yield 38%) as a red solid.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[NH:20][N:19]=[N:18][C:13]=2[N:14]=[C:15]([NH2:17])[N:16]=1>O>[C:3]1([CH2:2][O:9][C:11]2[C:12]3[NH:20][N:19]=[N:18][C:13]=3[N:14]=[C:15]([NH2:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]nnc2n1
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2[nH]nnc2n1
Reaction time: 16 h
Yield: 61.4 %

Procedure:
Sodium metal (3.7 g, 0.162 mol) was added in pieces to benzyl alcohol (117 ml, 1.13 mol) under nitrogen over 20 minutes. The reaction was then heated to 80° for 90 minutes. All of the sodium metal dissolved, and the reaction was left at room temperature for 16 hours. 7-Chloro-1H-1,2,3triazolo[4,5-d]pyrimidin-5-amine (9.23 g. 0.0541 mol) was then added, and the reaction was heated to 60° for 5 hours. The reaction was cooled and left at 5° for 16 hours. Water (500 ml) was added to dissolve the precipitate and then the mixture was extracted with ether (3×200 ml). The pH of the water layer was lowered to 7.0 with concentrated HCl and then to 5.5 with 1N HCl. The precipitate was filtered and dried at room temperature over P2O5 in vacuo to give 8.05 g of desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([NH:37]CCO)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:19]1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[NH2:37][CH2:18][CH2:19][N:11]1[C:10](=[O:15])/[C:9](=[CH:8]/[C:7]2[CH:16]=[CH:17][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)/[S:13][C:12]1=[O:14]
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 182.5 %

Procedure:
Compound 2 (1.26 g, 5.08 mmol), 2-(tritylamino)ethanol (2.00 g, 6.60 mmol) and triphenylphosphine (1.80 g, 6.86 mmol) were dissolved in 51 mL of anhydrous THF, and stirred at room temperature for 5 min. DIAD (1.3 mL, 6.60 mmol) was added to the reaction mixture and then stirred overnight at 45° C. The reaction mixture was diluted with ethyl acetate and washed with sat'd NH4Cl aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (30% ethyl acetate in hexanes) to afford 3 (75.0%, 2.71 g) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[OH:7][N:8]=[C:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CO>[ClH:1].[OH:7][N:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:11][CH2:10]1
Reactant: N#CCCl
Reactant: ON=C1CCNCC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CCl)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.63 ml of chloroacetonitrile was added to a solution of 23 mg of metallic sodium in 4 ml of absolute methanol, and the mixture was stirred for about 30 minutes at room temperature. 1.5 g of 4-hydroxyiminopiperidine hydrochloride were then added and the stirring was continued for 2 hours, during which time a precipitate separated out. 25 ml of anhydrous ether were added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with ether, giving 2.22 g of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)=[CH:23][CH:22]=3)[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:41](Cl)(=[O:50])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:44]1([CH2:43][CH2:42][C:41]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:25][CH:26]=2)[CH2:17][CH2:18][CH2:19][CH3:20])=[O:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCCCC(Nc1ccc(OCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(c1ccc(OC2CCCCO2)cc1)N(C(=O)CCc1ccccc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-{1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-pentyl}-amine (0.100 g, 0.22 mmol) and triethylamine (0.092 mL, 0.66 mmol) in 2 mL methylene chloride was added hydrocinnamoyl chloride (0.082 mL, 0.55 mmol), dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 585.1 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13]([CH3:21])([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:22](=[O:24])[CH3:23])[N:3]=1.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O>C(Cl)Cl>[Si:31]([O:24][C:22]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([NH:12][C:13]([CH3:21])([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH3:14])[C:2]([CH3:1])=[N:3]2)=[CH2:23])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12

Procedure:
A solution of 1-(2-methyl-3-((2-methyl-4-(methylsulfonyl)butan-2-yl)amino)quinoxalin-5-yl)ethanone (338c, 0.51 g, 1.46 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (0.50 mL, 2.20 mmol), and TEA (0.61 mL, 4.40 mmol) in DCM (14.68 mL) was stirred at 0° C. for 30 min when silyl enol ether was observed via lcms. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)quinoxalin-2-amine (338d) as a yellow oil. MS (ESI, pos. ion) m/z: 464.2 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[OH-:36].[Na+].OO.Cl>CCO.CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([NH2:20])=[O:36])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Temperature: 60 °C

Procedure:
To a solution of compound 54a (60 mg, 0.13 mmol) in EtOH (4 mL) and DMSO (1 mL) was added a 3N aqueous NaOH (0.06 mL, 0.18 mmol) and 30% hydrogen peroxide (0.3 mL). The reaction mixture was refluxed at 60° C. for 12 h. The reaction mixture was allowed to cool to rt and acidified with 2N HCl to pH˜2 and extracted with DCM (2×30 mL). The combined DCM layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (0-10% MeOH/DCM) to give the title compound 84. 1H-NMR (400 MHz, MeOH) δ (ppm): 3.83-3.87 (m, 4H), 4.27-4.32 (m, 4H), 5.62 (s, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.32-7.38 (m, 2H), 7.59 (ddd, J=8.4, 7.0, 1.5 Hz, 1H), 7.65-7.72 (m, 1H), 7.74-7.81 (m, 2H), 7.97 (d, J=8.8 Hz, 1H), 8.03 (dd, J=8.1, 2.2 Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 8.73 (d, J=1.5 Hz, 1H). (LCMS, ESI pos.) Calcd. for C26H23N7O3: 482.2 [M+H]. found 482.2.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:39](=[O:38])[CH2:40][OH:41])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)([OH:3])=[O:2].[Br:17]Br.CCCCCC>CC(O)=O>[Br:17][C:14]1[C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: BrBr
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(CC(=O)O)cc1OC
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
Methyl 4-carboxymethyl-2-methoxybenzoate 10c (12.7 g, 0.0567 mol) was dissolved in glacial AcOH (100 mL) and bromine (3.2 mL, 0.0624 mol, 1.1 eq) was added drop wise via a syringe, while maintaining the internal temperature between 20-25° C. After stirring for 4 h at RT, the AcOH was evaporated and the orange oil co-evaporated twice with toluene to give an orange solid. This material was triturated with CH2Cl2 and some of the precipitated product was removed by filtration. The rest of the product which remained in the filtrate was then concentrated, loaded on a silica gel column and eluted with 1% AcOH in EtOAc:hexane (6:4 ratio). The product was further purified by a second chromatography and re-crystallization from EtOAc:hexane to give pure methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate as white solid 10d (total amount 9 g, 52% yield).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.C(SC)(=S)O[CH:28]([C:30]1[C:31]([O:65][CH3:66])=[N:32][C:33](/[C:36](/[C:55]2[CH:60]=[CH:59][C:58]([C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:57][CH:56]=2)=[CH:37]/[C@H:38]2[CH2:42][CH2:41][C:40](=[O:43])[N:39]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])=[CH:34][CH:35]=1)[CH3:29].O>C1(C)C=CC=CC=1>[C:61]([C:58]1[CH:59]=[CH:60][C:55](/[C:36](/[C:33]2[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[C:31]([O:65][CH3:66])[N:32]=2)=[CH:37]\[C@@H:38]2[N:39]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[C:40](=[O:43])[CH2:41][CH2:42]2)=[CH:56][CH:57]=1)([CH3:63])([CH3:62])[CH3:64]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)OC(=S)SC)c(OC)n2)c(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2Cc2ccc(OC)cc2OC)c2ccc(C(C)(C)C)cc2)nc1OC
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Tributyltin hydride (91 μL) and azobisisobutyronitrile (8.5 mg) were added to a solution of O-[1-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)ethyl] S-methyl carbonodithioate (109 mg) in toluene (2 mL), and the mixture was stirred at 120° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (65 mg).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:7])[NH:5][N:6]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:5]1[C:4](=[O:7])[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:2]([Br:1])=[N:6]1
Reactant: COC(=O)CCl
Reactant: O=c1[nH]nc(Br)n1Cc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nc(Br)n(Cc2cccc(F)c2)c1=O

Procedure:
1.50 g (4.69 mmol) of the compound from Example 137A are stirred under reflux for 4 hrs together with 508 mg (4.69 mmol) of methyl chloroacetate and 1.30 g (9.4 mmol) of potassium carbonate in 33 ml acetonitrile. After cooling, the mixture is neutralized with 1 N hydrochloric acid and diluted with ethyl acetate. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and freed of the volatile components on the rotary evaporator. The residue is dissolved in 20 ml dichloromethane and absorbed onto 3 g of diatomaceous earth. After removal of the solvent on the rotary evaporator the solid is transferred to a silica gel chromatography column and the product purified by elution with cyclohexane/ethyl acetate (gradient 5:1→1:1). 1.36 g (84% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[CH:18][C:7]2[N:8]3[C@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:22][NH:23][CH2:24]2)=[CH:18][C:7]2[N:8]3[C@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2c(cc1OC1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of (R)-tert-butyl 3-((8-isopropyl-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)oxy)-3-methylazetidine-1-carboxylate ((enantiomer 2, SFC (Table 1, Method 24), Rt=9.756 min., 0.095 g, 0.213 mmol) in DCM (3 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give (R)-8-isopropyl-1-methyl-9-((3-methylazetidin-3-yl)oxy)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #121-2, Enantiomer 2, SFC (Table 1, Method 24), Rt=3.331 min, 0.085 g, 97%). LC/MS (Table 1, Method 5) Rt=2.175 min.; MS m/z: 345 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1.[CH2:14]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])[CH3:15].C(=O)=O>C(O)CCC>[CH2:14]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[C:7]3[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=3[N:5]=[C:4]([CH3:13])[N:3]=2)[CH2:23][CH2:24]1)=[O:18])[CH3:15]
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C=O
Solvent: CCCCO
Product: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3)CC1
Yield: 87 %

Procedure:
A mixture containing 1 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Khim. Geterotsikl. Soed. 1976, 681), 10 ml of n-butanol and 1.58 g of 1-ethoxycarbonylpiperazine is refluxed under protection against moisture and carbon dioxide, then evaporated. The residue is triturated with water and the product precipitated at 0° to 4° C. is filtered, washed with water and ether and dried to give 1.4 g (87%) of product, m.p.: 197°-198° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:16]2[C:11](=[C:12]([CH3:21])[C:13]([CH3:20])=[C:14]([OH:19])[C:15]=2[CH2:17][CH3:18])[O:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5]1.Cl>C1COCC1.O1CCOCC1>[CH2:17]([C:15]1[C:14]([OH:19])=[C:13]([CH3:20])[C:12]([CH3:21])=[C:11]2[C:16]=1[CH:4]([NH:3][O:2][CH3:1])[CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1)[CH3:18]
Reactant: CCc1c(O)c(C)c(C)c2c1C(=NOC)CC1(CCC1)O2
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCc1c(O)c(C)c(C)c2c1C(NOC)CC1(CCC1)O2
Reaction time: 8 h

Procedure:
5-Ethyl-6-hydroxy-7,8-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one O-methyloxime was dissolved in 10 mL of THF. To this solution at 0° C. was added BH3/pyrine complex (2.27 mL). Subsequently, a solution of 9 mL of HCl in dioxane (4.0 M) was added over a period of 1 hour. The reaction mixture was allowed to stir overnight. The mixture was extracted with ethyl acetate and washed with saturated NaHCO3. After evaporation of the solvents, the residue was purified by flash chromatography eluted with 5-8% ethyl acetate in hexane to give 136.4 mg of the product 5-ethyl-4-(methoxyamino)-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol. 1H-NMR (300 MHz, CDCl3) δ=4.40 (b, 1H), 4.30 (m; 1H), 3.66 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 2.70-1.60 (m, 6H), 1.25 (t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=146.3, 145.2, 126.1, 124.1, 123.4, 114.1, 76.8, 61.8, 52.4, 36.0, 35.0, 32.9, 19.2, 14.9, 13.9, 13.4, 12.4 ppm. MS: (m/z)=245.1 (M−NH2OMe+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=O)[C:22](=CN(C)C)[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH:28][CH2:29][CH2:30][N:31]([C:33](OC(C)(C)C)=O)[NH2:32]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:33]5[N:31]([CH2:30][CH2:29][OH:28])[N:32]=[CH:21][C:22]=5[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=C1C(=O)CCc2c1sc1ncnc(Nc3ccc(F)c(Cl)c3)c21
Reactant: CC(C)(C)OC(=O)N(N)CCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one (10.6 g, 0.026 mol) was heated to near homogeneity in dioxane (250 mL). The heat was turned off and nitrogen was bubbled through the murky solution for ˜20 min while it cooled. The reaction flask was then evacuated and filled with nitrogen three times. In a separate flask, tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate (13.9 g, 0.079 mol) was dissolved in toluene, concentrated in vacuo to a residue, redissolved in dioxane, and sparged with nitrogen for ˜10 minutes. The solution of tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate was evacuated and filled with nitrogen three times and then was cannulated into the flask containing the enamine. The resulting mixture became a clear red solution upon heating in an oil bath at ˜80° C. After 6 h the reaction mixture was concentrated in vacuo to half its original volume. Xylenes (250 mL) was added and the mixture was again concentrated to half the original volume. Xylenes (250 mL) was added and the mixture was concentrated to half the original volume a final time. During the solvent swap, a yellow-orange solid precipitated. The resulting slurry was submerged in an ice-bath and TFA (200 mL) was added dropwise via an addition funnel. The slurry became a brown-red solution that was allowed to stir overnight at room temperature. Two liquid phases were present the next morning. Solvent (˜200 mL) was removed in vacuo at ˜40° C. The remaining mixture (˜300 mL) was diluted with EtOAc (500 mL) and washed twice with 500 mL portions of 1.0 N NaOH. Significant emulsions formed during the final base wash, so more EtOAc (500 mL) was added with brine (100 mL) before collecting the aqueous layer. The organic layer was then washed with brine (2×300 mL). The organic layer was filtered through a small pad of silica gel (˜1″ diameter×2″) and the pad was washed with EtOAc (750 mL). The filtrate was concentrated to a total volume of ˜200 mL, resulting in the precipitation of solid. The slurry was filtered by vacuum filtration on a Buchner funnel and the resulting solid was allowed to dry overnight on the filter. An orange solid was obtained (7.25 g, 66%, >98% regioisomeric purity by 1H-NMR). 1H NMR (DMSO-d6) δ 8.56 (s, 1H), 8.38 (s, 1H), 7.88 (m, 1H), 7.66 (s, 1H), 7.61 (m, 1H), 7.40 (t, 1H), 4.93 (t, 1H), 4.16 (t, 2H), 3.73 (dt, 2H), 3.42 (t, 2H), 3.10 (t, 2H); LCMS RT=2.76 min; [M+H]+=416.4.
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[C:8]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:7]3=[CH:6][C:5]=2[C:4](=O)[N:3]1[CH:24]([CH3:26])[CH3:25].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:26][CH:24]([N:3]1[CH2:4][C:5]2[CH:6]=[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:8]3=[CH:9][C:10]=2[CH2:2]1)[CH3:25]
Reactant: CC(C)N1C(=O)c2cc3c(cc2C1O)CCN(C(=O)OC(C)(C)C)CC3
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1Cc2cc3c(cc2C1)CCNCC3
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of 1,1-dimethylethyl 1-hydroxy-2-(1-methylethyl)-3-oxo-2,3,5,6,8,9-hexahydroazepino[4,5-f]isoindole-7(1H)-carboxylate (1.0 g) and triethylsilane (0.95 ml) in DCM (20 ml), at 0° C., TFA (10 ml) was added dropwise and the mixture stirred for 1 h. the mixture was neutralized with 2M aqueous Na2CO3 and washed with ether discarding the organic layer. Then the aqueous layer was made basic with NaOH and extracted with DCM. The organic solution was washed with brine, dried over Na2SO4 and concentrated to afford a pale yellow solid (0.6 g, 88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)SCC[C@@H]2N
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)c1ccc2c(c1)SCC[C@@H]2NC(=O)OCc1ccccc1

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (S)-4-aminothiochromane-7-carboxylic acid methyl ester (3.80 g) and benzyloxycarbonyl chloride (3.65 ml), the objective (S)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (5.02 g) was obtained as colorless crystals.