Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1([C:18]([C:21]2(F)[C:26](F)(F)[C:25](F)(F)[C:24](F)(F)[C:23](F)(F)[C:22]2(F)F)(F)F)[C:7](F)(F)[C:6](F)(F)[C:5](F)(F)[C:4](F)(F)[C:3]1(F)F>FC1C(F)=C(F)C(F)=C(F)C=1F>[C:2]1([CH2:18][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC1(F)C(F)(F)C(F)(F)C(F)(C(F)(F)C2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C2(F)F)C(F)(F)C1(F)F
Solvent: Fc1c(F)c(F)c(F)c(F)c1F
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
Diphenylmethane (0.24 g) was placed in a reactor chamber and contacted with helium and fluorine according to the reaction conditions listed in Table 2. Bis(perfluorocyclohexyl) difluoromethane was obtained in 93% yield (0.72 g) by recrystallization in hexafluorobenzene (C6F6). 19F NMR of the product dissolved in C6F6 gave two broad multiplets centered around +120 and +180 ppm from CFCl3 which integrated for eleven and one, respectively. Infrared analysis utilizing a KBr disk gave absorptions at 1180 (broad), 1000 (m), 960 (m), 500 (w), and 480 (w) cm-1. The highest molecular weight fragment observed in the mass spectrum m/e 331, corresponded to the parent minus one perfluorophenyl. Freezing point depression of bis(perfluorocyclohexyl) difluoromethane in C6F6 gave a moleculr weight of 550 g/mol (theoretical: 612 g/mol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[C:38]([CH3:39])=[C:37]2[C:32]([CH:33]=[C:34]([NH2:40])[CH:35]=[CH:36]2)=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:40][C:34]2[CH:35]=[CH:36][C:37]3[C:32]([CH:33]=2)=[N:31][N:30]([CH3:29])[C:38]=3[CH3:39])=[N:3][CH:4]=1
Reactant: Cc1c2ccc(N)cc2nn1C
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CC4)CCN(C(=O)OC(C)(C)C)CC5)n3)cc2nn1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a suspension of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (659.8 mg, 1.59 mmol) and 2,3-dimethylindazol-6-amine hydrochloride (580.6 mg, 2.94 mmol) in n-BuOH (6 mL) was added DIPEA (755.5 mg, 5.79 mmol). The reaction mixture was stirred at 150° C. under microwave radiation for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a yellow solid (169.7 mg, 19.8%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=[O:21])=[O:20])([C:9]([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(OCCOCCO)CCC>O>[C:6]([S:19]([N:22]([CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[CH2:3][CH2:2][C:1]([OH:5])=[O:4])(=[O:20])=[O:21])([C:9]([C:12]([C:15]([F:16])([F:17])[F:18])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7]
Reactant: CN(C)CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: CCCCOCCOCCO
Product: CN(C)CCCN(CCC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 125 °C

Procedure:
An acrylic acid Michael addition reaction was then run according to the general procedure given in U.S. Pat. No. 5,144,069 (Stern et al.). 50 g (0.12 mole) of the purified C4F9SO2N(H)C3H6N(CH3)2, 16.4 g (0.23 mole) of acrylic acid and 0.2 g of phenothiazine (free radical polymerization inhibitor) were added to a 250-mL three-neck flask equipped with an air stirrer and thermometer. The resulting mixture was heated to 125° C. and was allowed to react for 6 hours. After this reaction period, a positive solubility check of the product in water of pH 7 indicated that the Michael addition reaction was essentially complete. While still mixing, a solvent blend of 18 g of diethylene glycol monobutyl ether and 42 g of deionized water was added and the mixture was allowed to cool to room temperature. The water solubility test was run again with the same positive result, showing good conversion to the desired Michael addition product, C4F9SO2N(C2H4COOH)C3H6 (CH3)2.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[CH:14]([NH2:17])([CH3:16])[CH3:15].C>C(O)C>[CH:14]([N:17]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])([CH3:16])[CH3:15]
Reactant: CC(C)N
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: C
Solvent: CCO
Product: CC(C)N1C(=O)Cc2ccccc2C1=O
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of homophthalic acid (90 g., 0.5 mole) and isopropylamine (59 g., 1 mole) was heated by an oil bath to 175°-180° C. for 90 minutes. The hot mixture was then poured into 600 ml. of ethanol, treated with carbon black and filtered. The mixture was concentrated to about 300 ml. and slowly cooled to room temperature. 2-Isopropylisoquinoline-1,3 (2H, 4H)-dione precipitated and was collected by filtration, 46 g. (45% yield), m.p. 86°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:28])=[CH:20][CH:21]=1
Reactant: CCCN=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in N,N-dimethylformamide (3 ml), propyl isocyanate (0.2 ml) was added, and the admixture was stirred at 80° C. for 24 hours. Water was added to the reaction mixture, the admixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 59 mg of the title compound (yield: 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][NH2:15])[C:8]=2[CH:16]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](Cl)=[O:34]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][NH:15][C:33](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccn1
Reactant: NCCNc1nsc2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccc([N+](=O)[O-])cc12)c1ccccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
N1-(5-Nitrobenzo[d]isothiazol-3-yl)ethane-1,2-diamine (92 mg, 0.38 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (148 μL, 1.3 mmol). The solution was cooled on an ice-water bath and a solution of 2-picolinoyl chloride hydrochloride (76 mg, 2.7 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2.5 h while warming to room temperature. The solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N-(2-(5-nitrobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (100 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3): 8.58 (m, 1H), 8.40 (m, 1H), 8.22 (d, 1H), 7.83 (t, 1H), 7.45 (m, 2H), 7.40 (m, 2H), 3.80 (m, 2H), 3.60 ppm (m, 2H). MW=343 confirmed by LC-MS, tr=11.59 min (Method Y) MH+=344.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.C1C(=O)N([Cl:32])C(=O)C1>>[Cl:1][C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[C:18]=3[Cl:32])[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)cc(OC)c1OC
Product: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)c(Cl)c(OC)c1OC

Procedure:
Chlorination of 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine) (CF 2137) with NCS (1.5 equivalents) was done following the general procedure 3 to give the title compound: HPLC RT was 6.244 min. 1HNMR (CDCl3): δ 6.53 (s, 1H), 5.70 (s, 2H), 5.48 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]1[C:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1>O1CCCC1.CS(C)=O>[O:23]1[CH2:4][C:13]21[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[CH:16]=[CH:17][C:18]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]2=1
Reactant: C[S+](C)C
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C1=Cc2ccccc2C2(CO2)c2ccccc21
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 4.6 g. of sodium hydride (57%) and 100 ml. of dimethylsulfoxide is heated under nitrogen at 75° C. for 50 minutes and the resulting mixture treated by addition of 40 ml. tetrahydrofuran and then cooled to 0° C. Over a period of 3 minutes there is then added 10.2 g. of trimethylsulfonium iodide in 100 ml. of dimethylsulfoxide, the resulting mixture stirred for one minute and there is then added over a period of 10 minutes a solution of 16.4 g. of dibenzo[a,d]cyclo-hepten-5-one in 40 ml. of tetrahydrofuran. The resulting mixture is kept overnight at temperature of 5° C. and then stirred for 3 hours at room temperature (20° C.). The mixture is then poured onto 3 times its volume of ice water, extracted twice each with 600 ml. of pentane, the organic phases combined, washed four times with water, dried over anhydrous sodium sulfate and evaporated in vacuo to crystallize spiro[dibenzo[ a,d] cycloheptene-5,2'-oxirane], m.p. 90°-91° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH:16]([C:18](Cl)=[O:19])[CH2:15][C:14]2=[O:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C1C=CC=CC=1>[CH2:24]([NH:27][C:18]([CH:16]1[CH2:17][N:13]([C:5]2[CH:4]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[C:14](=[O:21])[CH2:15]1)=[O:19])[CH2:25][CH3:26]
Reactant: CCCN
Reactant: O=C(Cl)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Solvent: c1ccccc1
Product: CCCNC(=O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 81.1 %

Procedure:
3.59 g (0.01 mole) of the 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid chloride, produced according to Example 4, paragraph 1, is dissolved in 400 ml of benzene, and 1.2 g (0.02 mole) of N-n-propylamine is added to the solution. After subsequent processing as described in Example 4 there is obtained 3.1 g (81% of theory) of 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid-N-n-propylamide; m.p. 152.5° - 154° C. Analysis for C16H16F6N2O2 (molar weight 382.32):
Reaction SMILES: C(SC=C)=C.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C.O=O.C(S[C:31]1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([OH:50])[CH:45]=2)[C:34]2([CH:41]3[CH2:42][CH:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)[O:33][O:32]1)C.O1CCO1.[C:55]1([OH:61])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C12CC3CC(CC(C3)C1=O)C2>C(Cl)Cl>[OH:50][C:46]1[CH:45]=[C:44]([C:31]2([O:61][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:34]3([CH:41]4[CH2:40][CH:39]5[CH2:38][CH:37]([CH2:36][CH:35]3[CH2:43]5)[CH2:42]4)[O:33][O:32]2)[CH:49]=[CH:48][CH:47]=1
Reactant: Oc1ccccc1
Reactant: CCSC1(c2cccc(O)c2)OOC12C1CC3CC(C1)CC2C3
Agent: C1COO1
Agent: C=CSC=C
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Solvent: ClCCl
Product: Oc1cccc(C2(Oc3ccccc3)OOC23C2CC4CC(C2)CC3C4)c1
Temperature: -78 °C

Procedure:
The vinyl sulfide of Example 1(b) (0.106 g) was irradiated for 10 min in 20 mL of CH2Cl2 containing a few crystals (<1 mg) of methylene blue with continuous oxygen bubbling at -78° C. using a 1000 W Na lamp. TLC indicated that the vinyl sulfide was consumed. N-Chlorosuccinimide (0.047 g) was added and the mixture maintained at -78° C. for 15 minutes. Phenol (83 mg) was added and the solution warmed to room temperature. Progress of the reaction was monitored by the appearance of a new material by TLC (20% ethyl acetate in hexane) which emitted blue light when the plate was heated and by observing the color of chemiluminescence from an aliquot of the reaction solution reacted with 0.1 M TBAF in DMSO. The yellow emission of dioxetane 1 was gradually replaced by the blue emission of dioxetane 11 over a period of an hour. The solution was concentrated and the residue chromatographed on a silica prep. TLC plate with 20% ethyl acetate in hexane. The major band was isolated and found to contain a mixture of phenol, ca. 60 mg of dioxetane 11 and ca. 5 mg of adamantanone. Dioxetane 11: 1H NMR (CDCl3) δ1.09-1.19 (m), 1.25-1.35 (m), 1.45-1.54 (m), 1.56-2.14 (m), 2.26 (br s), 3.28 (br s), aromatic peaks could not be resolved from residual phenol.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:8][S:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:12]([CH3:13])[C:11]([NH:10][C:9]3[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=3)=[O:15])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: COC(=O)c1cscc1NC(=O)C(C)Cl
Product: CC(Oc1ccc(-c2ccc(F)cc2)cc1)C(=O)Nc1cscc1C(=O)O

Procedure:
In analogy to Example 2, the title compound was prepared using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester and 4′-fluoro-biphenyl-4-ol. MS (m/e): 384.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][OH:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)Cl>C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH:17]=[O:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Yield: 88.9 %

Procedure:
A solution of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carbo x-amide (8.50 g, 31.3 mmol), Dess-Martin periodinane (14.6 g, 34.4 mmol) and DCM (400 mL) was stirred at 25° C. for 3 h. The reaction was diluted with a saturated sodium bicarbonate solution and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (7.50 g, 89%). LCMS for C10H6ClFN3O3(M+H)+: m/z=270.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:34][C:35]([F:53])([F:52])[O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[C:48]3[CH:49]=[CH:50][S:51][C:47]=3[CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:44]2[CH2:45][CH2:46][C:47]3[S:51][CH:50]=[CH:49][C:48]=3[CH:43]2[C:40]2[CH:39]=[CH:38][C:37]([O:36][C:35]([F:34])([F:53])[F:52])=[CH:42][CH:41]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(C2NCCc3sccc32)cc1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CCc3sccc3C2c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117 %

Procedure:
4-Methoxybenzoic acid (0.64 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (25 ml) and 1-hydroxybenzotriazole (0.71 g, 5 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol). The resulting mixture was stirred at room temperature for 30 minutes. 4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.5 g, 5 mmol) followed by N,N-diisopropylethylamine (1.4 ml, 8.4 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (10 ml) was added and the mixture was extracted with diethyl ether (3×20 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluting with a mixture of ethyl acetate and heptane (1:2). The pure fractions were pooled and concentrated in vacuo. The residue was crystallised from a mixture of methyl tert-butyl ether and heptane to afford 2.13 g (98%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:54])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:55]([NH:58][C:59]1[S:60][C:61]([S:65](Cl)(=[O:67])=[O:66])=[C:62]([CH3:64])[N:63]=1)(=[O:57])[CH3:56]>>[CH3:2][O:3][C:4](=[O:54])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[S:65]([C:61]1[S:60][C:59]([NH:58][C:55](=[O:57])[CH3:56])=[N:63][C:62]=1[CH3:64])(=[O:66])=[O:67])=[O:23])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(C)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(C)c(Cl)c2)cc1)CO3
Yield: 59.2 %

Procedure:
(S)-2-({(S)-3-[4-(3-Chloro-4-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (15 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (11 mg) according to General Procedure E to give (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3-chloro-4-methyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)propionic acid methyl ester (11 mg), which was hydrolyzed according to General Procedures N and B to give the title compound (5 mg). LCMS: (m/z) 893.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14](SC)=[N:15][CH:16]=3)[N:11]([CH3:21])[C:10]2=[O:22])[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1)C(OO)=O.[NH3:34].O1CCOCC1>C(Cl)Cl>[NH2:34][C:14]1[N:13]=[C:12]2[N:11]([CH3:21])[C:10](=[O:22])[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=3)[CH2:18][C:17]2=[CH:16][N:15]=1
Reactant: N
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c(N)c1)C2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(N)nc21
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of Example A1 (400 mg, 1.3 mmol) in CH2Cl2 (5 mL) was added 3-chloroperoxybenzoic acid (mCPBA) (430 mg, 2.5 mmol) in one portion. After stirring for 2 h, the reaction mixture was quenched with aq NaHCO3 and aq NaHSO3. The organic layer was separated and was washed with brine, dried Na2SO4) and concentrated in vacuo. The crude product was dissolved in DMSO (2 mL) and was treated with a solution of ammonia in dioxane (2 M, 30 ml, 60 mmol). The mixture stirred overnight at RT. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 7-amino-3-(3-amino-4-fluorophenyl)-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (276 mg, 77% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1 H), 6.96 (dd, J=8.4, 6.6 Hz, 1 H), 6.68 (dd, J=6.3, 2.1 Hz, 1 H), 6.52 (br s, 2 H), 6.44 (m, 1 H), 5.18 (s, 2 H), 4.48 (s, 2 H), 3.19 (s, 3 H); MS (ESI) m/z: 289.2. (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=2[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Yield: 103.9 %

Procedure:
To a slurry of (Z)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate (5000 mg, 14311 μmol) in 30 mL of MeOH was added [(1S,1S,2R,2R′) Rh(duanphos)cod]BF4 (101.1 mg, 143.1 μmol) followed by an additional 15 mL of methanol. The mixture was purged with hydrogen 3 times and then sealed at 50 psi of H2After 3 hours reaction the reaction was concentrated and purified by silica gel chromatography to provide (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate (5000 mg, 99.43% yield) as a colorless oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:19]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23]([F:30])[C:20]=1[C:21]#[N:22]>C1COCC1>[F:30][C:23]1[C:20]([C:21]#[N:22])=[C:19]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
LiHMDS (1.0M in THF, 38 mL, 38.0 mmol) was added dropwise to a stirred solution of aniline (1.86 g, 19.9 mmol) in anhydrous THF (30 mL) under a nitrogen atmosphere at −78° C. After 10 min stirring at −78° C., a solution of 2,6-difluoro-3-nitrobenzonitrile (3.5 g, 19.0 mmol) in THF (15 mL) was added and stirring at −78° C. continued for 30 min. The crude mixture was quenched with water and diluted with EtOAc. The resulting emulsion was filtered through a pad of Celite® and the organic fraction separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (2.7 g, 55%). 1H NMR (CDCl3, 400 MHz): δ 9.94 (1H, br s), 8.51 (1H, dd, J=9.50, 5.88 Hz), 7.51-7.21 (5H, m), 6.68 (1H, dd, J=9.50, 7.46 Hz).