Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([NH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[O:17])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].O1CCCC1.O.[OH-].[Li+]>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][C:7]12[CH2:13][CH:11]3[CH2:10][CH:9]([CH2:14][C:5]([C:3]([OH:4])=[O:2])([CH2:12]3)[CH2:6]1)[CH2:8]2)=[O:17]
Reactant: COC(=O)C12CC3CC(CC(NC(=O)c4ccccn4)(C3)C1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC12CC3CC(C1)CC(C(=O)O)(C3)C2)c1ccccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 93.3 %

Procedure:
To a round bottom flask was added 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester (24.8 g, 78.9 mmol), tetrahydrofuran (250 mL), water (250 mL) and lithium hydroxide monohydrate (14.9 g, 355 mmol) and the mixture was stirred vigorously at room temperature for 25 hours. The crude mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran, then the aqueous solution was diluted with water (200 mL) and the pH was adjusted to about 3-4 by adding solid citric acid monohydrate. A voluminous white precipitate appeared which was filtered, washed with water and dried under high vacuum at 50° C. to afford 22.1 g (93%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid, as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.18 (d, J=7.7 Hz, 1H), 7.97 (br s, 1H), 7.85 (td, J=7.8, 1.8 Hz, 1H), 7.42 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 2.35-2.31 (m, 2H), 2.31-2.25 (m, 2H), 2.25-2.09 (m, 4H), 2.00-1.86 (m, 4H), 1.80-1.64 (m, 2-11). ESI-MS m/z: 301.0 (M+H)+.
Reaction SMILES: CC1(C)[O:22][C:6]2=[C:7]([CH3:21])[N:8]=[CH:9][C:10]([CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[C:5]2[CH2:4][O:3]1.C(O)=O>C1COCC1.O>[OH:22][C:6]1[C:5]([CH2:4][OH:3])=[C:10]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:9]=[N:8][C:7]=1[CH3:21]
Reactant: Cc1ncc(COc2ccc(C#N)cc2)c2c1OC(C)(C)OC2
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1O
Yield: 91.8 %

Procedure:
A solution of 4-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethoxy)-benzonitrile (12) (3.10 g, 10 mmol) in THF (30 mL) was heated in a solution of 10% formic acid in water for 2 hours at 80° C. Upon evaporating the solvent, the crude product was washed with a mixture of ethyl acetate and hexane (1:2, 200 mL) to give 4-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (13) (2.48 g, 92% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([OH:10])=[O:9].C(O)C.[CH2:14]([NH:21][C@@H:22]([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:14]([NH:21][CH:22]([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([OH:10])=[O:9]
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: O=C1CCC2C1[C@H]2C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a solution of crude (±)(6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid (11.9 g, 84.9 mmol, assume 100% potency) in 119 mL of 6:1 ethyl acetate:ethanol at reflux is added 18 g (85.1 mmol) of (S)—N-benzyl-α-methylbenzyl-amine. Upon dissolution, the mixture is allowed to cool optionally followed by seeding at 52° C. Upon cooling to room temperature and stirring an additional 13.5 h, the crystals are collected and washed with 6:1 ethyl acetate:ethanol (2×48 mL). Drying in vacuo gave 10.8 g (36%, 77% de) of the resolved salt as a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:47])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)[CH:36]=[CH:37][CH:38]=4)[N:25]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(C)(C)C.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]3[N:29]4[N:30]=[CH:31][CH:32]=[C:28]4[CH:27]=[C:26]([C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)[CH:36]=[CH:37][CH:38]=4)[N:25]=3)=[CH:21][CH:22]=2)=[O:47])=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cccc(-c3cc4ccnn4c(Nc4ccc(NC(=O)c5ccc(CNC(=O)OC(C)(C)C)cc5)cc4)n3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(-c3cc4ccnn4c(Nc4ccc(NC(=O)c5ccc(CN)cc5)cc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (4-{4-[5-(4′-methoxy-biphenyl-3-yl)-pyrazolo[1,5-c]pyrimidin-7-ylamino]-phenylcarbamoyl}-benzyl)-carbamic acid tertbutyl ester (0.124 g) and trifluoroacetic acid (TFA)(1.5 ml) in dichloromethane (7 ml) is stirred 3 h at ambient temperature. The reaction mixture is evaporated, coevaporated with toluene and dried at high vacuum. Crystals (0.136 g) are obtained in quantitative yield and a melting temperature at 235-240° C.
Reaction SMILES: C[O:2][C:3](=[O:14])[C@H:4]([CH3:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH2:6]([NH:5][C@H:4]([C:3]([OH:14])=[O:2])[CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](C)NCc1ccccc1
Solvent: O
Product: C[C@H](NCc1ccccc1)C(=O)O

Procedure:
333 g (1.72 mmol) of N-benzylalanine methyl ester (J. Chem. Soc. 4374 (1952)) are heated under reflux overnight with 860 ml of water. Product which has deposited is filtered off with suction and the filtrate is extracted once with tert.-butyl methyl ether. The aqueous solution is concentrated and the crystals obtained are dried over phosphorus pentoxide in a desiccator with the first crystal fraction.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.[I-].[K+]>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]3[CH2:9][N:8]([CH3:7])[CH2:20][CH2:19][C:11]2=3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c3c(c4ccccc42)CN(C)CC3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
Potassium tert-butoxide (0.95 g, 8.5 mmol) was placed under argon and suspended in 1 mL of anhydrous DMF. To it was added 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (17) (1.5 g, 8.1 mmol) dissolved in 3 mL of DMF upon which the reaction turned a deep orange in color. The reaction was stirred at room temperature for 15 min after which 4-bromomethyl-benzoic acid methyl ester (1.8 g, 8.1 mmol) was added in 1 mL of DMF along with approximately 5 mg of potassium iodide. The reaction then turned a light orange in color. The reaction was stirred at 80° C. for two hours after which the reaction was quenched by the addition of 15 mL of water. The pH was adjusted to approximately 12 with 2N NaOH and the organic products were extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the title compound (1.7 g, 61%) as a yellow oil. 1H NMR (400 MHz, CD3OD): δ 7.83 (d, 2H, J=8.3 Hz), 7.33 (d, 1H, J=7.8 Hz), 7.23 (m, 3H), 7.07 (m, 1H), 6.97 (m, 1H), 4.59 (s, 2H), 4.01 (s, 2H), 3.82 (s, 3H), 2.90 (t, 2H, J=5.5 Hz), 2.84 (t, 2H, J=5.3 Hz), 2.48 (s, 3H). 13C NMR (100 MHz, MeOD): δ 167.1, 147.5, 134.9, 130.4, 129.2, 128.1, 128.0, 127.4, 120.4, 119.2, 177.7, 108.3, 108.1, 65.4, 51.0, 50.0, 40.2, 29.2, 20.3. ESI-MS (m/z): [M+H]+ 335.2 m/z.
Reaction SMILES: I[CH3:2].[CH3:3][O:4][CH:5]([O:13][CH3:14])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S-:12])[N:7]=1.[Na+]>CO>[CH3:14][O:13][CH:5]([O:4][CH3:3])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:2])[N:7]=1
Reactant: COC(OC)c1ccnc([S-])n1
Reactant: CI
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to the crude solution of sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) (156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining the reaction temperature below 28° C. using an ice-water bath for cooling. The resulting mixture was stirred at room temperature for 16 h. After removal of the solvent under reduced pressure, the residue was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was concentrated under reduced pressure and the crude residue purified by passing through a short silica gel pad and washing with diethyl ether (200 mL) to afford 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) as a brown oil (53.7 g, 150 g theoretical, 35.7%). LC-MS m/z 201 (M+1). Reference: WO 2006/0097341A1, pg 67.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)[CH2:2][CH3:3].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14]>>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]([C:7]2[S:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:8]=2)[OH:14])[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCCc1ccsc1
Product: CCCc1csc(C(O)c2cccc(Br)c2)c1

Procedure:
3-n-Propylthiophene and 3-bromobenzaldehyde were used and treated in a manner similar to Reference Example 7-(1) to give 3-bromophenyl-4-n-propyl-2-thienyl methanol. APCI-Mass m/Z 293/295 (M+H−H2O).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:11].Cl[N:13]1[C:18](=[O:19])N(Cl)C(=O)N(Cl)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:36](OCC)(=[O:38])C>ClC1C=CC=CC=1>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:9])[CH3:10])=[CH:7][C:2]=1[CH2:1][NH:13][C:18](=[O:19])[O:38][CH3:36]
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CCOC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COC(=O)NCc1cc(C(C)=O)ccc1Cl
Temperature: 87.5 °C

Procedure:
25.0 g of 4-chloro-3-methylacetophenone and 13.9 g of trichloroisocyanuric acid were suspended in 150 ml of chlorobenzene. A catalytic amount of azobisisobutyronitrile was added thereto, followed by stirring under heating at from 85 to 90° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and insoluble matters were collected by filtration. The filtrate was washed with an aqueous sodium hydroxide solution and water in this order, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue, 12.2 g of potassium cyanate and 14.4 g of methanol were added to 150 ml of N,N-dimethylformamide, followed by stirring under heating at 90° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=3/1). The obtained crystals were washed with isopropyl ether to obtain 6.0 g of methyl N-(2-chloro-5-acetylbenzyl)carbamate as colorless crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].F[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[CH3:23])[C:19](=[O:24])[N:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH:17]=[CH:16]2>CC(N(C)C)=O>[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=2[CH3:23])[C:19](=[O:24])[N:18]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:17]=[CH:16]3)[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@H](N)CC4)c(C)cc3c2=O)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.48 g (9.75 mmol) of trans-4-aminocyclohexanol hydrochloride in 20 ml of dimethylacetamide where added 1.95 g (48.77 mmol) of sodium hydride (60%) and the mixture was stirred for 15 minutes. Subsequently 2.90 g (9.75 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in 30 ml of dimethylacetamide were added and the reaction mixture was heated to 80° C. for 2 days. After cooling the mixture was poured into 300 ml of ice water and the precipitated crude product was purified by chromatography. First the remaining starting material was eluted with ethyl acetate/heptane (2:1) und finally the desired product was eluted by pure methanol giving 1.98 g 6-(trans-4-amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([N+:10]([O-:12])=[O:11])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(=Cc1ccc(Br)cc1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A solution of 30.0 g (162 mmol) of 4-bromobenzaldehyde, 116 mL (1.6 mole) of nitroethane, and 37.5 g (486 mmol) of ammonium acetate in 200 mL of toluene was heated under a Dean and Stark trap for 18 hours. The mixture was then cooled to 80° C., 1 mL of concentrated sulfuric acid was added, and the mixture was stirred at 80° C. for 2 hours. The mixture was then cooled to ambient temperature and washed with 200 mL of brine. The organic layer was separated and the aqueous layer was extracted three times with 60 mL of diethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from methanol to afford 18.7 g (47%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:12](C(=O)C)=[CH:11][CH:10]=[CH:9][C:8]=2[CH:16]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[C:19]([O:23][Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C1C[O:39]CC1>>[CH:11]1([CH2:12][C:7]([C:1]2[CH:2]=[CH:3][C:4]([CH2:19][OH:23])=[CH:5][CH:6]=2)=[O:39])[CH2:10][CH2:9][CH2:8][CH2:16]1
Reactant: C1CCOC1
Reactant: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Reactant: CC(=O)c1cccc(C=O)c1C1CCCCC1
Agent: [H-]
Agent: [Li+]
Product: O=C(CC1CCCC1)c1ccc(CO)cc1
Yield: 90 %

Procedure:
Following the procedure of Example F, the product of Example K 2.5 g (0.011mole) was reduced in 35 mls of THF containing 3.5 g of lithium tri-tert-butoxy aluminum hydride to give 2.25 g of the title compound (90% yield).
Reaction SMILES: O=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17]C)=O)=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1.CN1CC2NC3C=CC=C4C(=O)[NH:34][N:35]=C(C=2C=34)C1.[CH3:37][C:38]([CH3:40])=O>>[CH:38]([N:4]1[CH2:5][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[C:15](=[O:17])[NH:34][N:35]=[C:2]([C:14]=2[C:13]=34)[CH2:3]1)([CH3:40])[CH3:37]
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Reactant: CC(C)=O
Product: CC(C)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 45 was prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and acetone according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.83 (s, 1H), 7.43 (d, 1H, J=8.4 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.08 (dd, 1H, J=8.4, 7.6 Hz), 3.78 (s, 2H), 3.26 (s, 2H), 2.93-2.96 (m, 1H), 1.04 (d, 6H, J=6.4 Hz). MS (ESI) m/e [M+1]+ 269.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5](/[CH:6]=[CH:7]/[S:8]([N:11]([CH2:18][CH:19](OCC)[O:20]CC)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[S:8]([N:11]([CH2:18][CH:19]=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:9])=[O:10])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CN(CC(OCC)OCC)S(=O)(=O)/C=C/c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)CN(CC=O)S(=O)(=O)/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a mixed solution of the compound obtained in Step 1 (2.00 g), chloroform (9.5 ml) and water (9.5 ml) was added trifluoroacetic acid (13.5 ml) under cooling with ice water. The reaction mixture was stirred at room temperature for 4 hours, adjusted to pH 8 with saturated aqueous solution of sodium hydrogencarbonate and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and thereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain the title compound (1.27 g).
Reaction SMILES: Br[C:2]1[N:3]([CH:24]([CH3:26])[CH3:25])[C:4]2[C:9]([N:10]=1)=[C:8]([C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=2.[CH3:27][Zn]C.CO>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:24]([N:3]1[C:2]([CH3:27])=[N:10][C:9]2[C:4]1=[N:5][C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[N:7][C:8]=2[C:11]1[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=1)([CH3:26])[CH3:25]
Reactant: CC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc2n1C(C)C
Temperature: 65 °C
Yield: 47 %

Procedure:
To a solution of 5-(8-bromo-9-isopropyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (30 mg, 0.072 mmol) and Pd(dppf)Cl2, (3 mg, 5% mmol) in 3 ml of anhydrous dioxane, was added slowly dimethyl zinc (210 μl, 1.0 M in heptane solution) in a sealed tube. The mixture was heated to about 65° C. MeOH was added drop wise and the solvents removed in vacuo. EtOAc was added to the residue and the resulting solution washed with 1 M HCl, water, brine and then dried over Na2SO4. The solvent was removed and the crude mixture was subjected to flash chromatography on silica gel to obtain 5-(9-isopropyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine 8 mg in a yield of 47%. 1H NMR, MeOD: 9.40 (s, 2H), 4.81 (m, 1H), 3.89 (m, 4H), 3.82 (s, 4H), 3.71 (s, 3H), 1.73 (d, 6H). m/z: 355.16 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[Cl:19])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.CN(C)C=O>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([Cl:19])[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:22])=[CH2:25]
Reactant: Cn1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=COCCONC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10ff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.010 mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL, 0.077 mmol), and EDCl (19 mg, 0.10 mmol) are dissolved into dimethylformamide (1.0 mL) and allowed to stir under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture is diluted with EtOAc, washed with water (3×), 10% potassium carbonate (2×), saturated ammonium chloride, brine, dried (Na2SO4), and concentrated under reduced pressure to give 39 mg of 85% pure material. MS APCI (−) m/z 497, 501 (M−, Br pattern) detected.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[CH2:11]([O:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][C:26]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:28][N:27]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (230 mg, 1.73 mmol) described in Manufacturing Example 13-1-3 in anhydrous tetrahydrofuran (20 mL) was added (2-benzyloxy-pyridin-5-yl)-acetohydroximoyl chloride (1.00 g, 3.61 mmol) described in Manufacturing Example 12-1-5 under nitrogen atmosphere at room temperature. Triethylamine (965 μL, 6.92 mmol) was added dropwise to the mixture and stirred for 1.5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (470 mg, 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[CH:4][N:3]=1.[CH:25]1[C:35]2[CH:34]=[CH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH:30]([C:40]3[C:41](=[O:47])[NH:42][C:43](=[O:46])[NH:44][CH:45]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1>>[CH:25]1[C:35]2[CH:34]=[CH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH:30]([C:40]3[C:41](=[O:47])[NH:42][C:43](=[O:46])[N:44]([C:2]4[N:7]=[C:6]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([C:14]5[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=5)=[CH:4][N:3]=4)[CH:45]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CSc1nc(Cl)ncc1-c1ccc(CC(=O)OC)cc1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Product: COC(=O)CSc1nc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)ncc1-c1ccc(CC(=O)OC)cc1

Procedure:
The subtitle compound was prepared from the product of step (iv) (0.58 g) and the product of example 1 step (iv) (0.48 g) by the method of example 2 step (i). Purification was by chromatography eluting with 2% methanol in chloroform. Yield 0.4 g.