Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:29]=[O:30])[CH:8]=2)[S:3]1
Reactant: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C=O)cc32)cc1
Temperature: -10 °C
Reaction time: 5 h

Procedure:
To a cold (-78° C.) solution of 2,2-dimethyl-4(tol-4-yl)-6-bromo-thiochrom-3-ene (Compound N, 280 mg, 0.81 mmol) in THF (5 mL) was added n-BuLi in hexane (1.6 M solution, 0.66 mL). The mixture was gradually warmed to -10° C. over 25 min. and recooled to -78° C. To this solution was added DMF (80 mg, 1.1 mmol) and stirred at ambient temperature for 5 hours. The reaction was quenched by adding water (10 mL), ethyl acetate (100 mL), and the organic layer was washed with brine (10 mL), dried and the solvent removed by distillation. The crude material was used in the next reaction without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:26][N:27]1[C:31]2[CH:32]=[C:33]([C:36]([OH:38])=O)[CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.CCN(C(C)C)C(C)C.[CH2:48]([O:50][C:51](=[O:65])[C@H:52]([OH:64])[CH2:53][C@H:54]([NH2:63])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([Br:62])=[CH:58][CH:57]=1)[CH3:49]>>[CH2:48]([O:50][C:51](=[O:65])[C@H:52]([OH:64])[CH2:53][C@H:54]([NH:63][C:36]([C:33]1[CH:34]=[CH:35][C:30]2[N:29]=[N:28][N:27]([OH:26])[C:31]=2[CH:32]=1)=[O:38])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([Br:62])=[CH:60][CH:61]=1)[CH3:49]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(Br)cc1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
HCTU (837 mg, 2.0 mmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (362 mg, 2.0 mmol) and the mixture was stirred at room temperature for 10 minutes. DIPEA (529 μL, 3.0 mmol) and (2R,4R)-4-amino-5-(4-bromophenyl)-2-hydroxy-pentanoic acid ethyl ester (320 mg, 1.0 mmol) were then added and the resulting mixture was stirred at room temperature for 15 minutes. The mixture was concentrated in vacuo and the resulting residue was purified (C18 column, 55 g, 20-70% MeCN in water with 5% TFA) to yield the title compound as a white solid 365 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2C(O)=O)=[CH:4][CH:3]=1.C([N:16](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:16])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(F)cc1

Procedure:
To a solution of the product from step c) (2.6 g) and triethylamine (2.7 ml) in acetone/water (10:1, 33 ml) at 0° C. was added ethyl chloroformate (2.0 ml) over 5 min. The solution was maintained at 0° C. for 30 minutes before addition of sodium azide (1.52 g) in water (6 ml). After a further hour, water (350 ml) was added and the reaction mixture extracted with toluene (3×100 ml). The organic extracts were combined and dried, then heated at reflux for 2 hours behind a blast screen. After cooling the solution, 6M HCl (50 ml) was added and the mixture heated at reflux for 3 hours. Water (150 ml) was added and the aqueous phase basified with 2M NaOH (aq), then extracted into dichloromethane (3×100 ml). The organic phase was dried and concentrated to give the subtitle compound as a colourless oil (1.31 g).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:20])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.C(N(CC)CC)C>CN1CCN(C)C1=O>[CH3:1][C@H:2]1[C@@H:7]([N:8]2[C:12]3=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:20])[CH2:6][CH2:5][N:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=2)[CH2:3]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: C[C@@H]1CNCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: C[C@@H]1CN(c2ccc(C#N)cn2)CC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 160 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of rel-1-[(3R,4S)-3-methyl-4-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (20 mg) in 1,3-dimethyl-2-imidazolidinone (0.5 mL) were added 6-chloronicotinonitrile (20 mg) and triethylamine (41 μl), The mixture was stirred at 160° C. for 2 hours. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give rel-6-[(3R,4S)-3-methyl-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinyl]nicotinonitrile (13 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:37])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:36])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:3][C:4]([OH:6])=[O:5].[Na].O.Cl>CCCCCO>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:37])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:36])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCCCCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)O

Procedure:
82 g of 3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22,26-octacosaheptaenoic acid was dissolved in 1 l of n-amyl alcohol and 74 g of metallic sodium was added portionwise while the solution was vigorously stirred. After metallic sodium was completely dissolved, the reaction solution was poured into iced water and was made acidic by adding 300 ml of 6 N hydrochloric acid. It was then extracted with 1 l of n-hexane, washed with water, dried and concentrated. 78 g of colorless, oily 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenoic acid was obtained as the crude product. The product was then added dropwise to 500 ml of an ethereal suspension of 10 g of lithium aluminum hydride while being cooled by ice and stirred. After stirring was continued for 30 minutes, 10 ml of water with 10 ml of a 15% caustic soda solution, and 30 ml of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 ml of ether. The filtrate was concentrated and the concentrate was defined by silica gel column chromatography, providing the captioned 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol as a colorless oily matter.
Reaction SMILES: N1C=CN=C1.[I:6]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:27][C@H:28]([CH2:38]O)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[F:27][C@H:28]([CH2:38][I:6])[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@H](F)CO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](F)CI
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Imidazole (19.8 g, 0.29 mol) was dissolved in methylene chloride (900 mL) at room temperature. Iodine (73.9 g, 0.29 mol) was added and the reaction mixture was stirred for 10 min at room temperature and then cooled to 0° C. Triphenylphosphine (76.3 g, 0.29 mol) was added portionwise over 10 min such that the internal temperature remained below 10° C. A solution of tert-butyl (2S)-2-fluoro-3-hydroxypropylcarbamate (45.0 g, 0.23 mol) in methylene chloride (300 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 h. The reaction mixture was filtered through a pad of Celite® and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with methylene chloride. This procedure afforded tert-butyl (2S)-2-fluoro-3-iodopropylcarbamate as a colorless oil (42.5 g, 62%). 1H NMR (300 MHz, CDCl3) δ 4.80-5.10 (br s, 1H), 4.58-4.72 (m, 0.5H), 4.42-4.56 (m, 0.5H), 3.48-3.70 (m, 1H), 3.20-3.46 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[N:22])[CH:8]=2)[CH2:3]1.[C:24]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]([CH3:24])[C:16](=[O:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[N:22])[CH:8]=2)[CH2:3]1
Reactant: CC1(C)Cc2ccc(C#N)cc2C(Oc2cc[nH]c(=O)c2)C1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1ccc(OC2c3cc(C#N)ccc3CC(C)(C)C2O)cc1=O
Reaction time: 2 h

Procedure:
A mixture of 310 mg of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-1,2,3,4-tetrahydro-3-naphthol, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethylsulfate is boiled for 2 hours. The mixture is filtered and the filtrate is worked up in the customary manner to give 2,2-dimethyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-1,2,3,4-tetrahydro-3-naphthol.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CC#N>[C:13]([C:7]1[CH:6]=[C:5]([N:4]([CH2:3][C:2]([F:15])([F:16])[F:1])[CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:10]=[CH:9][C:8]=1[C:11]#[N:12])#[N:14]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C#N
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C#N)c1
Temperature: 85 °C
Yield: 56.7 %

Procedure:
A solution of 4-[(2,2,2-trifluoroethyl)amino]-1,2-benzenedicarbonitrile (0.020 g, 0.089 mmol) in MeCN (3 mL) was treated with Cs2CO3 (0.078 g, 0.24 mmol) and methyl bromoacetate (0.037 g, 0.24 mmol) and heated at 85° C. under nitrogen for 8 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (20-100% CH2Cl2-hexanes gradient) and the product crystallized from CH2Cl2-hexanes to give 0.015 g (58% yield) of the title compound as a white solid: MS (ES) m/z 296 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(Cl)cc(C#N)nc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
To a solution of 4-chloro-7-methylquinoline-2-carbonitrile (6.66 g, 33 mmol) in CCl4 (160 mL) was added NBS (6.46 g, 36.3 mmol) and benzoyl peroxide (800 mg, 3.3 mmol). The mixture was heated under reflux overnight, cooled to room temperature and evaporated to dryness. The reaction mixture was purified by flash chromatography on silica gel (eluting solvent: dichloromethane/hexane, 9/1) to provide the title compound (8.46 g). 1HNMR (400 MHz, acetone-d6): δ 8.37 (d, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.05 (d, 1H), 4.95 (s, 2H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4].Cl.Cl[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:25][CH2:26]3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:27]=1)[CH3:4]
Reactant: Clc1ccncc1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCNCC1)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3ccncc3)CC1)C2=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
Compound 24 (42.0 mg, 0.101 mmol) obtained in Example 24, and 4-chloropyridine.hydrochloride (22.6 mg, 0.151 mmol) were dissolved in ethanol (0.5 mL), and the mixture was stirred at 140° C. for 2 hours under microwave (CEM; Discover, 300 watts) irradiation after adding triethylamine (140 μL, 1.01 mmol). The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography, and crystallized from diisopropylether to give the title compound (Compound 25) (17.0 mg, 40%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[Na+].Cl>O.C(#N)C>[ClH:5].[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: ClCCCN1CCOCC1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
5 ml acetonitrile, 2.3 ml (23 mmol) of 1-bromo-3-chloropropane and 1 ml (11.5 mmol) of morpholine were added successively into a reaction flask. The mixture was stirred for 1 h, and 0.5 ml of 5% NaOH solution was added. After stirring at room temperature for 12 h, 3 ml concentrated hydrochloric acid and 10 ml water were added into the mixture. The lower layer was discarded, and the upper layer was alkalified with 5% NaOH and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, then filtrated. The filtrate was concentrated to dry in a reduced pressure, and a small amount of ethanol/NaOH solution was added dropwise into the residue. The mixture was shaken and placed in a refrigerator for standing, then concentrated to dry in a reduced pressure to obtain 1.4 g white solid with the yield of 60%. m.p. 168-170° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](I)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COCCOC.[Cl:46][C:47]1[CH:56]=[C:55]2[C:50]([C:51](B3OC(C)(C)C(C)(C)O3)=[CH:52][CH:53]=[N:54]2)=[CH:49][CH:48]=1.[OH-].[Ba+2].[OH-].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:51]2[C:50]4[C:55](=[CH:56][C:47]([Cl:46])=[CH:48][CH:49]=4)[N:54]=[CH:53][CH:52]=2)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccnc3cc(Cl)ccc23)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(I)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(-c2ccnc4cc(Cl)ccc24)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy)-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (258.4 mg, 0.0003752 mol) in 1,2-Dimethoxyethane (3.0 mL, 0.029 mol) was added 7-chloroquinoline-4-boronic acid pinacol ester (0.158 g, 0.000546 mol), barium hydroxide (0.228 g, 0.00133 mol), water (0.5 mL, 0.03 mol) and Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol), and the mixture was heated at 90° C. overnight. The reaction was cooled, quenched by addition of water and the mixture was extracted with DCM (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 30% EtOAc/hexanes) to obtain 180 mg (66.2%) mg. Reference: Cammidge, A. N.; Crepy, K. V. L. Tetrahedron, 2004, 60, 4377-4386.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=4[CH:29]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=3[CH:29]=2)[CH2:15][C:14]2[CH:30]=[CH:31][C:11]([C:10]#[C:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:12][CH:13]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Product: COc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The title compound was prepared following the procedure B using 7-({4-[(4-methoxyphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropionyl chloride as a beige solid (63%). 1H NMR (CDCl3) δ 7.91 (d, J=8.3 Hz, 1H), 7.41 (m, 4H), 7.12 (d, J=8.1 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 4.87 (s, 2H), 3.80 (s, 3H), 2.15 (t, J=6.9 Hz, 2H), 1.70 (s, 6H), 1.40-1.61 (m, 9H), 0.95 (m, 2H). HPLC, Rt: 5.78 min (purity: 99.3%).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH3:25]>CN(C)C=O>[CH2:24]([N:3]1[CH2:2][CH2:1][N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4]1)[CH3:25]
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN2c3ccccc3NC(=O)CC2C1
Temperature: 60 °C

Procedure:
To a solution of Example 1D (30 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (57 mg, 0.41 mmol) and bromoethane (10.3 μl, 0.14 mmol). The reaction was warmed to 60° C. for 14 hours. Excess potassium carbonate was filtered off. The solution was passed through a PS-isocyanate cartridge (Silicycle, 2 g) to trap leftover starting material. The solution was concentrated and purified by preparative HPLC with a gradient of acetonitrile and 0.1% trifluoroacetic acid in water to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.19-7.24 (m, 1H), 7.14-7.18 (m, 1H), 7.09-7.13 (m, 1H), 7.01 (dd, J=7.78, 1.37 Hz, 1H), 3.52-3.64 (m, 3H), 3.32-3.39 (m, 2H), 3.19-3.27 (m, 2H), 2.97-3.10 (m, 2H), 2.66 (dd, J=13.73, 7.02 Hz, 1H), 2.09 (d, J=13.12 Hz, 1H), 1.27 (t, J=7.32 Hz, 3H); MS (ESI) m/z 246.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+]>CN(C)C=O.O>[F:16][C:13]1[CH:14]=[CH:15][C:7]2[NH:6][C:3](=[O:4])[CH2:2][O:10][C:9](=[O:11])[C:8]=2[CH:12]=1
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COC(=O)c2cc(F)ccc2N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2.52 g(13.75 mmol) of bromoacetyl bromide was added for 10 min below 40° C. to the solution having 1.94 g(12.5 mmol) of 2-amino-5-fluorobenzoic acid dissolved in 4 ml of dimethyl formamide. The mixed solution was stirred for 30 min, and the solution having 1.12 g of sodium hydroxide dissolved in 28 ml of water was added. The mixture was slowly heated to 60° C. for 1 hr, then maintained at about 60° C. for 1 hr, and cooled to 5° C. Finally, a crystalline solid of 7-fluoro-4,1-benzooxazepine-2,5-(1H, 3H)-dione of melting point 186° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20]1[N:34]([C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:33][CH:32]=2)[N:35]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNc1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as colorless solid. MS (ESI): m/z=528.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Li])CCC.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 1-ethoxycarbonylpiperazine in 400 ml dry tetrahydrofuran is cooled to -65° and 61.5 ml of 2.1M solution of n-butyllithium in hexane is added dropwise over a period of 15 minutes. The mixture is stirred for 15 minutes and a solution of 16.44 ml of chlorotrimethylsilane in 68 ml of tetrahydrofuran is added dropwise over a period of 15 minutes. The mixture is then allowed to warm up to room temperature overnight and evaporated to dryness. Ethyl ether is added, the solids are filtered off, the filtrate is evaporated to dryness and the residue is distilled to give 1-ethoxycarbonyl-4-trimethylsilylpiperazine, b.p. 102°-107°/0.1 mm/Hg.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([C:20]([OH:22])=O)[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]>C(Cl)(Cl)Cl>[CH3:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([C:20]([Cl:3])=[O:22])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2

Procedure:
176.5 g of thionyl chloride were introduced into a balloon flask provided with a condenser. Then, in portions, 135 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added under heating at 40°-45° C. The mixture was heated under reflux and then treated with 250 cm3 chloroform. The precipitate was dried off and washed with chloroform.
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(N=C=S)ccc1-c1cnn(C)c1
Reactant: N
Product: COc1cc(NC(N)=S)ccc1-c1cnn(C)c1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
Step K (4): Methanolic ammonia (2.0 M, 20 mL, 40 mmol) was added to a flask charged with 4-(4-isothiocyanato-2-methoxyphenyl)-1-methyl-1H-pyrazole (1.46 g, 5.95 mmol). After 3 h, the reaction mixture was concentrated in vacuo. The solid was triturated with diethyl ether. The solid was collected by vacuum filtration and dried under high vacuum to afford 1-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)thiourea (1.35 g, 86% yield). LC-MS (M+H)+ 263.1.