Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](OCC)=[O:12])=[CH:5][C:4]=1[F:16])#[N:2].[BH4-].[Na+]>C(O)C>[F:16][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)CCc1ccc(C#N)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(CCCO)cc1F
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step C (140 mg, 0.71 mmol) in 3.5 mL of ethanol at 0° C. was added sodium borohydride (84 mg, 2.1 mmol). After 45 minutes, another portion of sodium borohydride was added, and the mixture was stirred overnight. The reaction was quenched with saturated NH4Cl solution, concentrated in vacuo, and partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the alcohol which was sufficiently pure for use in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([NH:33]C(=O)C)([CH2:31][OH:32])[CH2:29][OH:30])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[ClH:37]>>[ClH:37].[NH2:33][C:28]([CH2:27][CH2:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)([CH2:31][OH:32])[CH2:29][OH:30]
Reactant: CC(=O)NC(CO)(CO)CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: NC(CO)(CO)CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
A slurry of N-(4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-1-hydroxy-2-(hydroxymethyl)butan-2-yl)acetamide (0.205 g, 0.405 mmol) in 6 mL 5N aq. HCl was heated to 120° C. in a sealed tube. A clear yellow solution resulted, with a white precipitate forming after 1 h. The mixture was heated overnight to give a gray mixture, which was cooled and filtered through a glass frit, rinsing with water and EtOH, and the solid was dried in vacuo to give 2-amino-2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)propane-1,3-diol hydrochloride as an off-white solid. MS (ESI) m/z: calculated: 463.2; Observed: 464.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][CH2:19][C:20](Cl)=[O:21])[CH3:17]>CC(C)=O>[CH2:16]([O:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:21])[CH3:17]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CCOCC(=O)Cl
Solvent: CC(C)=O
Product: CCOCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 51.2 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro5-methyl-3(2H)-pyridazinone were stirred with 14.7 g (0.12 mole) of ethoxyacetyl chloride and 400 ml of absolute acetone for 10 hours at room temperature. The product was filtered off under suction at 10° C., washed with cold acetone and dried at 70° C. under reduced pressure. 14.8 g (51%) of 6-[p-(ethoxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li]CCCC.[CH:15](OC)=[O:16]>C1COCC1>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:15]=[O:16]
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: COC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(F)c1Cl
Temperature: -74 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,4-dichloro-1-fluorobenzene (100 g, 0.606 mol) in THF (1.4 L) under nitrogen at −78° C., was added a 2.5 M solution of n-BuLi in hexanes (267 mL, 0.666 mol) dropwise over a period of 30 min, maintaining the temperature between −70 to −78° C. After 1.5 h stirring at −78° C., methyl formate (72.6 mL, 1.21 mol) was added slowly, and the reaction mixture was stirred overnight, warming up to rt. The reaction was quenched with sat. aqueous NH4Cl (200 mL) and the organic layer was separated. The organic solvents were removed by distillation at atmosphere pressure and the crude material which contained a small amount of THF was crystallized from hexanes to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:39][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:37])(=[O:36])=[N:10][C:11](=[O:35])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CO)cc3)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CBr)cc3)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-{[4-(hydroxymethyl)phenyl] (methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (0.1 g, 0.195 mmol) and CBr4 (0.097 g, 0.293 mmol) were dissolved in CH2Cl2 (0.485 mL) and the resulting solution was cooled to 0° C. PPh3 (0.858 g, 0.293 mmol) was dissolved in CH2Cl2 (0.250 mL) and then added dropwise to the 0° C. reaction mixture. Subsequently the reaction was allowed to warm to room temperature and stir for ˜1.5 h. The reaction was then diluted with CH2Cl2 (5 mL) and the resulting organic mixture was washed with a saturated aqueous solution of NaHCO3 (5 mL), then with brine (5 mL). The organic layer was dried anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then taken on without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:5][C:4]=1[C:17]([F:19])([F:18])[F:20])#[N:2]
Reactant: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)(COS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 5 g (17.35 mmol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2,3-dihydroxy-2-methyl-propionamide in 50 ml of dry pyridine was cooled to 0° C. and 8.86 g (34.70 mmol) of 4-bromo-benzenesulfonyl chloride was added in small portions. The mixture was stirred at 0° C. for 5 h, then diluted with 200 ml of dichloromethane, washed three times with 50 ml of saturated aqueous sodium hydrogencarbonate, twice with 50 ml of 10% aqueous hydrochloric acid and 50 ml of brine. The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was crystallized from a 1:5 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:35]([N:24]1[CH2:25][CH2:26][N:21]([C@H:18]2[CH2:19][CH2:20][N:15]([C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:33])([F:1])[F:34])[CH:4]=3)=[O:14])[CH2:16][C@H:17]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(c1ccccc1)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1

Procedure:
The title compound, MS: m/e=590.2 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and benzoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[C:17]1([CH:27]=O)[C:26]2[C:20]([CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1.N1CCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:17]1[C:26]2[C:20]([CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1)(=[O:5])=[O:4]
Reactant: O=Cc1ccc2cccccc1-2
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNC1
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3cccccc1-3)C(=O)N2
Yield: 6.9 %

Procedure:
0.504 g 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (0.0021 mole) and 0.323 g azulene aldehyde (0.0021 mole) were dissolved in 30 mL dried ethanol. 1.5 mL pyrrolidine (1M) was then added and uniformly stirred at reflux temperature for two hours. After removal of dried ethanol, the results were extracted by dichloromethane and citric acid aqueous solution. The organic layer was collected, dried with anhydrous magnesium sulfate, filtered, concentrated under vacuum, and separated by silica gel column chromatography to give Compound 050 (E-form (0.0548 g), Z-form (0.1376 g)).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([N:17]1[CH2:31][C:20]2=[C:21]3[N:26]([N:27]=[C:19]2[CH2:18]1)[C:25]([CH3:28])=[C:24]([Cl:29])[C:23]([CH3:30])=[N:22]3)=[O:16])([F:7])[F:6])C.[NH4+:33].[OH-].CO>>[Cl:29][C:24]1[C:23]([CH3:30])=[N:22][C:21]2[N:26]([N:27]=[C:19]3[CH2:18][N:17]([C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][C:5]([F:6])([F:7])[C:4]([NH2:33])=[O:3])=[O:16])[CH2:31][C:20]3=2)[C:25]=1[CH3:28]
Reactant: CCOC(=O)C(F)(F)Oc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(F)(F)C(N)=O)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To [2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-difluoro-acetic acid ethyl ester (from example 102 step 1) (70 mg; 0.15 mmol; 1 eq.) was added NH4OH/MeOH and the reaction mixture was stirred at room temperature for 1.5 hour then concentrated in vacuo. The residue taken up in EA, washed sat. aq. NH4Cl, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (25 mg, 38%) as a white solid. HPLC (max plot) 99.6%, Rt 3.28 min. UPLC/MS: (MS+) 436.4 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:50][CH2:51][CH3:52])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])[CH:3]([CH3:5])[CH3:4]>C(O)(=O)C>[OH:1][CH:2]([C:6]1[N:7]=[C:8]([CH2:50][CH2:51][CH3:52])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])[CH:3]([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 99.1 %

Procedure:
Following a procedure similar to that described in Example 74(c), but using 1.36 g of 4-(1-hydroxy-2-methylpropyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (b) above] in 75% v/v aqueous acetic acid, 0.87 g of the title compound was obtained as a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])[N:10]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:24][CH2:25][CH2:26]Br>CN(C=O)C.O>[F:24][CH2:25][CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]2[N:8]=1
Reactant: FCCBr
Reactant: Nc1ccn2nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccn2nc(-c3ccccc3OCCF)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.3 %

Procedure:
To a solution of 2-(7-amino-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-phenol (250 mg, 1.10 mmol) in dry DMF (6 ml), K2CO3 (611 mg, 4.42 mmol) was added under positive nitrogen pressure and the mixture was stirred for 20 min at rt in a sealed tube. A solution of 1-fluoro-2-bromoethane (93 mg, 0.66 mmol) in DMF was added dropwise and the reaction mixture was heated for 8 h at 90° C. On completion of reaction (monitored by TLC), the mixture was cooled, diluted with water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude product. Purification by silica gel column chromatography using 2% MeOH in DCM as eluent afforded the desired product (200 mg, 66%) as off-white solid. LC-MS: m/z=273.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][CH:6]1[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:4].[Li+].[OH-]>CO.O>[C:17]([O:16][C:14]([NH:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC1CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid methyl ester (9.1 g, 31.9 mmol) in MeOH (260 mL) was added a solution of LiOH (3.34 g, 79.7 mmol) in water (80 mL). The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. Excess of solvent was removed and the residue was dissolved in water (100 mL). The aqueous solution was washed with ether, acidified to pH=3 with 2N HCl and extracted with EtOAc (2×150 mL). The combined organic phase was washed with brine, dried (Na2SO4) and evaporation of the solvent gave 8.4 g (97%) of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 0.71 (dd, J=4.0, 6.4 Hz, 1H), 0.95 (t, J=6.4 Hz, 6H), 1.35 (m, 1H), 1.43 (s, 1H), 1.49-1.55 (m, 1H), 1.64-1.69-(m, 2H) 3.23 (d, J=14.2 Hz, 1H), 3.40 (d, J=14.2 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:14]([OH:15])[C:13]([CH2:16][CH2:17][N:18]([CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH2:40][O:41][CH3:42])[CH:34]=[O:35].P(CCCC)(CCCC)CCCC.CN(C(/N=N/C(N(C)C)=O)=O)C>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@@H:14]([O:15][C:31]2[CH:32]=[C:33]([CH:34]=[O:35])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][O:41][CH3:42])[C:13]([CH2:16][CH2:17][N:18]([CH3:29])[S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[CH:12][CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(C=O)cc1O
Reactant: Cc1ccc(S(=O)(=O)N(C)CCC2=CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(C=O)cc1O[C@H]1C(CCN(C)S(=O)(=O)c2ccc(C)cc2)=CCC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.2 %

Procedure:
To a solution of alcohol 14 (190 mg, 0.43 mmol) and phenol 18 (102 mg, 0.56 mmol) in THF (6 mL) at −10° C. was added PBu3 (0.15 mL, 0.65 mmol) followed by tetramethylazodicarboxamide (TMAD) (111 mg, 0.65 mmol). The reaction mixture was slowly warmed to room temperature and was stirred for 22 hours. Solvent was evaporated under reduced pressure and purified by flash column chromatography on silica gel using [hexane/EtOAc (80:20)→hexane/EtOAc (50:50)] as eluent to isolate product 19b (130 mg, 0.22 mmol, 50%) as a clear oil.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.[C:17](=O)([O:20]C)[O:18][CH3:19]>C1COCC1>[CH3:19][O:18][C:17](=[O:20])[CH2:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: COC(=O)OC
Reactant: Cc1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of LDA (1.8M in THF/heptane/ethyl benzene, 223 ml, 401 mmol) was added slowly to a stirred solution of 2-chloro-4-methylpyridine (17.5 ml, 200 mmol) in dry THF (1 L) under N2, such that the internal temperature <−70° C. After 1 hour at this temperature, dimethyl carbonate (40 ml, 475 mmol) was added. After 30 minutes the reaction was transferred to a cold bath at −40° C., and then allowed to warm slowly to 0° C. After 1 hour at 0° C. the reaction was quenched with saturated aqueous NH4Cl (250 ml). The mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2). The combined extracts were washed with brine (×1), then dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 10-25% EtOAc/isohexane to give the ester (27.8 g, 75%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ: 3.63 (2H, s), 3.73 (3H, s), 7.17 (1H, dd, J 5.1, 1.4), 7.28 (1H, s), 8.34 (1H, d, J 5.1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([NH:32]C(=O)OC(C)(C)C)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]([CH2:28][CH3:29])[S:26](=[O:31])(=[O:30])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][C:4]=1[F:40]>O1CCOCC1.C(Cl)Cl.CO>[NH2:32][C@H:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([F:40])[CH:5]=1)[C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[C:20]3[CH:27]([CH2:28][CH3:29])[S:26](=[O:30])(=[O:31])[CH2:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CCC1c2c(ncnc2N2CCN(C(=O)[C@@H](Cc3ccc(Cl)c(F)c3)NC(=O)OC(C)(C)C)CC2)CS1(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CCC1c2c(ncnc2N2CCN(C(=O)[C@H](N)Cc3ccc(Cl)c(F)c3)CC2)CS1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
HCl in dioxane (4M, 2 mL) was added to a solution of tert-butyl (2R)-3-(4-chloro-3-fluorophenyl)-1-(4-(5-ethyl-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.005 g, 0.009 mmol) in DCM (2 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 5 hours. The solvent was removed to afford (2R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-(4-(5-ethyl-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one as the HCl salt (4 mg, 97%). LCMS: 482.1 [M+H+] (APCI+).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH2:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>CN(C=O)C.N1C=CC=CC=1>[Cl:19][CH2:20][C:21]([NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:17][C:21](=[O:22])[CH2:20][Cl:19])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Dissolve 1,8-diaminoanthraquinone (0.476 g, 2.0 mmol) in 20 ml DMF. Add pyridine (0.5 ml) as catalyst in an ice bath. Then add chloroacetyl chloride (0.5 ml, 6 mmol) into the solution, remove the ice bath, introduce nitrogen, protect from light, and stir the solution at room temperature for 24 hours. The reacted solution is poured into ice water (50 ml), filtered to get precipitate. At last, the precipitate is recrystallized to get yellow compound 3.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[CH3:16][N:17]1[C:26]2[NH:25][C:24]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:23]=3[N:22]([C:32]([CH:34]3[CH2:39][CH2:38][CH:37]([CH2:40][NH:41][C:42](=[O:50])[CH2:43][CH:44]4[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]4)[CH2:36][CH2:35]3)=[O:33])[CH2:21][C:20]=2[CH:19]=[N:18]1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2]([N:47]2[CH2:48][CH2:49][CH:44]([CH2:43][C:42](=[O:50])[NH:41][CH2:40][CH:37]3[CH2:36][CH2:35][CH:34]([C:32]([N:22]4[CH2:21][C:20]5[CH:19]=[N:18][N:17]([CH3:16])[C:26]=5[NH:25][C:24]5[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:23]4=5)=[O:33])[CH2:39][CH2:38]3)[CH2:45][CH2:46]2)=[O:3])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-Dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.58 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=658.5
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(O)(O)(=O)=O.Cl[C:27]1[NH:28][CH2:29][CH2:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:20][N:2]([CH3:1])[S:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:27]3[NH:31][CH2:30][CH2:29][N:28]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc(Cc2ccc(N)cc2)cc1
Reactant: ClC1=NCCN1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)O
Product: CN(C)S(=O)(=O)c1ccc(Cc2ccc(NC3=NCCN3)cc2)cc1
Yield: 164.4 %

Procedure:
A mixture of 4-(4-dimethylaminosulfonylbenzyl)-phenylamine (288 mg) and 2-chloro-imidazoline sulfate (110 mg) in 2-propanol was heated under reflux for 16 hours. A dilute solution of potassium carbonate was poured into the mixture and extracted with dichloromethane (4×15 mL). Solvents were evaported to give 2-[4-(4-dimethylaminosulfonylbenzyl)-phenyl]amino-imidazoline as a solid (320 mg).