Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH2:16][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (56.0 g) in 1,2-dichloroethane (550 mL) was added morpholine (37.8 mL) dropwise over 5 min. The mixture was cooled to 10° C. and was treated with NaBH(OAc)3 (64.3 g) in portions over 1 h. After a further 2 h, the mixture was warmed to room temperature, and a water bath was used to keep the temperature below 20° C. After 18 h, water (60 mL) was added while the temperature was kept under 20° C. by the addition of small amounts of ice. After 20 min, the mixture was basified to pH ˜10 with 1 N NaOH (450 mL) and the mixture was stirred for 10 min. The layers were separated, and the organic layer was washed with 1 N NaOH (150 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to yield the title compound as pale yellow viscous oil.
Reaction SMILES: C(N(CC)CC)C.[H-].[Ca+2].[H-].[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:17]1([C:23](Br)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[C:11]([O:16][C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)O
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Ca+2]
Agent: [H-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h

Procedure:
5.05 g (0.05 mol) of dry triethylamine distilled in the presence of calcium hydride was added to 20 ml of anhydrous ether distilled in the presence of lithium aluminum hydride, and the mixture was cooled with ice in a nitrogen atmosphere. 0.86 g (0.01 mol) of methacrylic acid was added thereto and the mixture was stirred. While cooling the mixture with ice, 3.23 g (0.01 mol) of triphenylmethyl bromide dissolved in 10 ml of anhydrous ether was added thereto, whereby the reaction rapidly proceeded and triethylamine hydrobromide was precipitated. The reaction was continued for 2.5 hr until the salt was completely precipitated, and the resulting crystal was recovered by filtration. When the solvent and excess triethylamine were distilled off, triphenylmethyl methacrylate was obtained as a crystal, which was then recrystallized from ether to give 3.07 g (yield: 92.9%) of a colorless prismatic crystal.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[CH3:24][Mg]I>C1COCC1>[CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([OH:22])[CH3:24])=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(C(C)O)cc3)no2)cc1
Temperature: 25 °C

Procedure:
A solution of 0.5 g (1.63 mmol) of Aldehyde 1 in 10 mL of THF was treated with 1.1 mL (3.3 mmol) of methylmagnesium iodide (3.0 M in diethyl ether) at −78° C. and was allowed to warm to rt over 30 min. The resulting mixture was quenched with 5 mL of 1 N HCl and was extracted with 30 mL of ethyl acetate. The extract was washed, dried and concentrated to afford the title compound: ESI-MS 323 (M+H); LC-1: 4.2 min.
Reaction SMILES: O.O.[Na+].[CH3:4][N:5]([CH3:9])[C:6](=[S:8])[S-:7].[NH2:10][C:11]1[N:16]=[C:15]([CH2:17]Cl)[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1>C(O)C.O>[NH2:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:17][S:8][C:6](=[S:7])[N:5]([CH3:9])[CH3:4])[N:16]=1
Reactant: CN(C)C(=S)[S-]
Reactant: COc1cc(CCl)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CSC(=S)N(C)C)nc(N)n1

Procedure:
18.5 g of dimethyldithiocarbamic acid sodium salt dihydrate and 17.4 g of 2-amino-4-chloromethyl-6-methoxypyrimidine are refluxed in 100 ml of ethanol for 30 minutes. After the mixture has been cooled, it is diluted with about 1 liter of water, and the product which has precipitated is separated and dried. The yield is 23.0 g (89% of theory) of 2-amino-4-methoxy-6-dimethylthiocarbamoylthiomethyl-pyrimidine, m.p. 118°-120° C.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7][C:8]1[C:9]2[O:16][CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1.CN([CH:20]=[O:21])C.[Cl-].[NH4+]>C1COCC1>[CH3:6][S:7][C:8]1[C:9]2[O:16][C:15]([CH:20]=[O:21])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CSc1ncnc2ccoc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncnc2cc(C=O)oc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Butyl lithium (as 1.6 M in hexanes, 7 mL) was added to a solution of 4-(methylthio)furo[3,2-d]pyrimidine (Intermediate 85) (1.21 g) in THF (25 mL) at −70° C. The reaction was stirred for 5 minutes, DMF (5 mL) added, and the reaction mixture allowed to warm to ambient temperature. 30% Saturated ammonium chloride solution (50 mL) was added and the mixture extracted into EtOAc (3×50 mL). The combined organics were washed with 50% saturated sodium carbonate solution (50 mL), water (50 mL), dried and the solvent removed to afford the title compound as a pale yellow solid (1.02 g) (the product contained 20% unreacted starting material but was used without further purification in subsequents steps);
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)C>O1CCOCC1.O>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH:5]=[O:4])=[CH:9][CH:10]=1
Reactant: CCOC(COc1ccc(CCO)cc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=CCOc1ccc(CCO)cc1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (5 mL) was added to a solution of 2-(4-(2,2-diethoxyethoxy)phenyl)ethanol [Aromatic Intermediate 12, step a] (0.76 g) in 1,4-dioxane (10 mL) and the resulting mixture was stirred for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were washed with water (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound, which was used directly. Yield 0.35 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.Cl>O>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: Cl
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Yield: 84.4 %

Procedure:
5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25-30° C. followed by 1.0 ml of 50% hydrochloric acid. The reaction mass was heated at 35- 40° C. for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40-45° C. to obtain 5.8 g of erlotinib hydrochloride.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[F:16][C:17]([F:35])([F:34])[C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1>C1COCC1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:30]1([OH:33])[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]3[N:22]([C:18]([C:17]([F:35])([F:34])[F:16])=[N:19][N:20]=3)[N:23]=2)[CH2:28][CH2:29]1
Reactant: Clc1ccccc1Br
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2Cl)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1.0M in THF, 10 mL, 10.00 mmol) was added dropwise to 1-bromo-2-chlorobenzene (1.91 g, 9.98 mmol) in THF (2.0 mL) cooled to 0° C. over a period of 10 minutes. The resulting solution was stirred at 0° C. for 1 hour then a 2.0 mL aliquot was added dropwise to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (400 mg, 1.40 mmol) in THF (10 mL) cooled to 0° C. over a period of 10 minutes. The resulting solution was stirred at 0° C. for 10 minutes then allowed to warm slowly to room temperature and stirred for a further hour. The reaction mixture was then quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc. The extract was washed with saturated brine, dried over MgSO4 and concentrated by evaporation, then purified by flash silica chromatography, eluting with EtOAc. Pure fractions were evaporated to dryness to afford 4-(2-chlorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (230 mg, 41%) as a colourless solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[O:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:23]([C@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[O:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic acid (1 ml) is added 30% hydrogen bromide-acetic acid solution (2 ml). The resulting mixture is allowed to stand for 1 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (10 ml). The solution is allowed to stand for 60 minutes at room temperature. After addition of acetic acid (1 ml), the mixture is chromatographed on MCI gel using water-methanol (1:2) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(R)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.13 g) as colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1)(=[O:3])N.[OH-].[Na+].C([O:34]CCOCCO)C>O>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:21]=2[CH2:22]1)([OH:3])=[O:34]
Reactant: NC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reactant: CCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 16 h

Procedure:
A mixture of 38.7 g of 2-[4-(5-carbamoyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine, 27.1 g of NaOH, 525 ml of water and 450 ml of diethylene glycol monoethyl ether is boiled, with stirring, for 16 hours. The mixture is cooled, the usual working up followed by acidification is carried out, and 2-[4-(5-carboxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)CC.[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:18]1[O:20][CH2:19]1.[ClH:34]>O>[ClH:34].[OH:20][CH:18]([CH2:17][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:19][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 0.5 h
Yield: 33108.2 %

Procedure:
L-arginine (17.4 g, 0.1 mmols) were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of propanol were added thereto. Dodecyl glycidyl ether [made by Sakamoto Yakuhin Kogyo Co., Ltd., 24.2 g (0.1 mols)] was added thereto dropwise over a period of 30 minutes while being heat-stirred under reflux, and the mixture was stirred as such under reflux, for 3 hours. After it was identified through TLC and gas chromatography that dodecyl glycidyl ether disappeared, the residue was neutralized with 10.1 g (0.1 mols) of 36-% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (Kieselgel 60 made by Merck & Co., Inc., eluent--mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 15.0 g of N-(2-hydroxy-3-dodecyloxypropyl)-L-arginine hydrochloride in a yield of 36.0%.
Reaction SMILES: [F:1][C:2]([F:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:15])[F:1])=[CH:19][CH:18]=1
Reactant: OCCCCCCCCCCC=C(F)F
Reactant: Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCCCCCCCCCCC=C(F)F)cc1
Yield: 37.2 %

Procedure:
A solution of 1.0 gram (0.0045 mole) of 12,12-difluoro-11-dodecen-1-ol (prepared in Example 5), 0.49 gram (0.0045 mole) of 4-methylphenol, 1.2 grams (0.0045 mole) of triphenylphosphine, and 0.79 gram (0.0045 mole) of diethyl azodicarboxylate in 25 ml of tetrahydrofuran was stirred, and the progress of the reaction was monitored by gas chromatographic analysis. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 25 ml of diethyl ether, and a solid precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.52 gram of 12,12-difluoro-11-dodecenyl 4-methylphenyl ether. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>N1C=CC=CC=1>[NH2:12][C:11]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:10]=1[NH:13][C:27]([C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2)=[O:28]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Product: CCCn1c(N)c(NC(=O)C23CC4CC(CC(C4)C2)C3)c(=O)n(CCC)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
At first, 10 g (44.3 mmol) of 1,3-dipropyl-5,6-diaminouracil was dissolved in 50 ml of pyridine, and 10.6 g (53.1 mmol) of adamantane-1-carbonylchloride was added by portions thereto at 0° C. After stirring for 30 minutes at 0° C., the mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate was added thereto. The residue was extracted with chloroform three times. The organic layers were combined, washed with a saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Then pyridine was removed from the residue by means of azeotropy with toluene to afford 19.5 g (yield: 100%) of 6-amino-5-(adamantane-1-carbonylamino)-1,3-dipropyluracil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH2:23])=[CH:12][CH:11]=3.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>>[NH2:22][C:18]1[O:19][CH2:20][CH2:21][C@:16]2([C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([F:8])[C:5]=3[O:9][C:10]3[C:15]2=[CH:14][C:13]([NH:23][C:31](=[O:32])[C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=2)=[CH:12][CH:11]=3)[N:17]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(Cl)nc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1c2cc(Cl)nc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
A mixture of (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.048 g, 0.143 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.025 g, 0.158 mmol) was purged with N2 followed by the addition of THF (2 mL) and MeOH (0.5 mL). 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.046 g, 0.158 mmol) was added in one portion and the resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with saturated NaHCO3, diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-4% MeOH/DCM and repurified by HPLC to afford (S)—N-(2′-amino-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.0258 g, 0.054 mmol, 37.9% yield). MS m/z=474.0 [M+H]+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].CC(N(C)C)=O.[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3.2 kgs. isatoic anhydride in 15 kgs. dimethylacetamide is added under nitrogen with stirring sodium hydride obtained from 880 gms. of a 57% dispersion in mineral oil, while maintaining the temperature below 25°C. The resulting mixture is heated to about 60°C. and held at about 55°-60°C. for 1 hour. The reaction mixture is then cooled to 20°-30°C. and to it is added 3.0 kgs. p-fluorobenzyl chloride. The mixture is then reheated to about 60°C. and held there for about 4 hours. It is then cooled again to 20°C. and to it is added 17.4 kgs. of ice and then 24 kgs. water. The mixture is stirred for 15 minutes, the solids collected by filtration, washed with several 2 kg. portions of water and then three times with 0.7 kg. diethylether. The washed solids are dried to obtain N-(p-fluorobenzyl)isatoic anhydride, m.p. 140°-143°C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:18]=[CH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C=CC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 1.8 %

Procedure:
To a solution of 2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydrospiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one (11.0 g) in chloroform (20 mL), trifluoroacetic acid (20 mL) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated. The residue was dissolved in methanol and hydrogenated with 4M hydrogen chloride/ethyl acetate in the presence of 20% palladium carbon at 1 atm of hydrogen for 14 hours. The catalyst was removed by filtration and the filtrate was concentrated. To the residue, aqueous 1N sodium hydroxide (5 mL), di-tert-butyl dicarbonate (655 mg) and dioxane (10 mL) were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (200 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][CH:8]([Cl:31])[C:9]([NH:11][C@H:12]([CH2:29][F:30])[C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[OH:14])=[O:10]>O1CCCC1>[NH2:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C@@H:13]([OH:14])[C@H:12]([NH:11][C:9](=[O:10])[CH:8]([Cl:31])[Cl:7])[CH2:29][F:30])=[CH:20][CH:19]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: -40 °C
Reaction time: 4 h
Yield: 15.2 %

Procedure:
To an ice cold solution of lithium aluminum hydride (0.048 g, 1.33 mmol, 4.0 eq) in tetrahydrofuran (10 mL) to −40° C. is added a solution of 2,2-dichloro-N-((1R,2S)-1-(4-(6-cyanopyridin-3-yl)phenyl)-3-fluoro-1-hydroxypropan-2-yl)acetamide (0.13 g, 0.34 mmol) in tetrahydrofuran (5 mL) at −40° C. Further lithium aluminum hydride is added (0.012 g, 0.33 mmol) three times and reaction mixture is stirred at −40° C. for 4 hours. The reaction mixture is quenched with saturated aqueous sodium sulphate and stirred for 15 minutes followed by filtration. The filtrate is evaporated in vacuo and the crude material purified by column chromatography on silica gel using methanol/CH2Cl2 and ammonia. To the solution of the crude in CH2Cl2 (5 mL) is added trifluoroacetic acid (0.5 mL) and stirred reaction mixture at room temperature for 15 min. Distilled out solvent under vacuum and washed the residue with diethyl ether, and the residue is dissolved in 10% methanol in CH2Cl2 and evaporated to dryness. Washed with n-pentane and dried under vacuum to get the title compound (20 mg): 1HNMR (400 MHz, CDCl3) δ: 4.24-4.25 (m, 2H), 4.28-4.32 (m, 0.5H), 4.40-4.44 (m, 0.5H), 4.56-4.60 (m, 0.5H), 4.68-4.72 (m, 0.5H), 4.92 (bs, 1H), 6.02 (bs, 1H), 6.52 (s, 1H), 7.48 (d, J=8.28 Hz, 2H), 7.57 (d, J=10.8 Hz, 1H), 7.73 (d, J=8.04 Hz, 2H), 8.17 (dd, J1=2.28 Hz, J2=8.08 Hz 1H), 8.28 (bs, 2H), 8.65 (d, J=8.84 Hz, 1H), 8.93 (d, 1H, J=2.2 Hz). m/z (Cl) 386 [M+H].