Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:14]=[C:13]([C:15]3[C:16]([NH:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[N:17][CH:18]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:41])[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[CH3:40][O:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:41])[N:10]=[C:9]([NH2:8])[CH:14]=3)=[CH:20][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:18][N:17]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)nc(C)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2cc(N)nc(C)n2)cn1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amine (137.7 mg, 0.190 mmol) and trifluoromethanesulfonic acid (50 μL, 0.563 mmol) in TFA (2.5 mL) was stirred at 80° C. for 2.5 h. The mixture was subsequently cooled to 25° C. and concentrated in vacuo. Sat. aq. NaHCO3 (25 mL) was carefully added to the residue (final pH about 8). The resulting suspension was sonicated for 2 min, and the precipitated solid was collected by vacuum filtration, washed with water (30 mL), and air-dried. The residue was taken up in MeOH, concentrated onto silica gel, and chromatographically purified (ISCO, 12 g, 0 to 10% MeOH/DCM) to yield 6-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-2-methylpyrimidin-4-amine (55.6 mg, 0.115 mmol, 60.4% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.80 (br. s., 1H); 8.37 (d, J=2.74 Hz, 1H); 8.14 (d, J=1.96 Hz, 1H); 8.10 (dd, J=8.90, 2.84 Hz, 1H); 7.86 (br. s., 1H); 6.76 (d, J=8.80 Hz, 1H); 6.70 (br. s., 1H); 4.95 (br. s., 2H); 3.93 (s, 3H); 3.43-3.56 (m, 2H); 3.26 (br. s., 4H); 2.78 (s, 3H); 2.63 (s, 3H); 2.58 (br. s., 4H). m/z (ESI, +ve ion) 485.1 (M+H)−.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]#[N:25])=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].CCN(C(C)C)C(C)C.Cl[C:36]1[N:41]=[CH:40][C:39]([CH:42]2[CH2:44][CH2:43]2)=[CH:38][N:37]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH:42]1([C:39]2[CH:38]=[N:37][C:36]([N:21]3[CH2:20][CH2:19][CH:18]([O:17][C:13]4[C:12]([C:24]#[N:25])=[N:11][N:10]([C:5]5[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=5)[C:15](=[O:16])[CH:14]=4)[CH2:23][CH2:22]3)=[N:41][CH:40]=2)[CH2:44][CH2:43]1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: N#Cc1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCN(c2ncc(C3CC3)cn2)CC1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
To a stirring solution of 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl (50 mg, 0.137 mmol) in NMP (2 mL) at room temperature under argon was added DIPEA (53.1 mg, 0.411 mmol) and 2-chloro-5-cyclopropylpyrimidine (31.7 mg, 0.205 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 27 mg (38.8%) of 4-(1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.50-0.66 (m, 2H) 0.82-0.98 (m, 2H) 1.64-1.79 (m, 1H) 1.83-1.99 (m, 2H) 1.99-2.16 (m, 2H) 3.60-3.90 (m, 2H) 3.96-4.25 (m, 2H) 4.56-4.87 (m, 1H) 6.31 (s, 1H) 7.41-7.50 (m, 1H) 7.50-7.60 (m, 1H) 7.73 (d, J=2.20 Hz, 1H) 8.05-8.18 (m, 2H). MS (ESI) 483 (M+H).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[F-].[K+].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]=1[C:8]#[N:9]
Reactant: Sc1ccccc1
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(F)c(F)c(Sc2ccccc2)c(C#N)c1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile and 0.87 g of potassium fluoride were dissolved in 10 ml of acetonitrile. After cooling the mixture to a temperature of 0° C. by an ice-water bath, 1.1 g of phenyl mercaptan was dropwise added by a syringe. While mixture was maintained at a temperature of about 0° C., the mixture was stirred for 8 hours and the solvent was then distilled off. A 50 ml amount of water was added to the mixture and potassium fluoride was dissolved. The mixture was extracted with chloroform, and the extract was dried with magnesium sulfate. The chloroform was distilled off in vacuo and the resultant liquid was then distilled in vacuo to obtain 1.8 g (63% yield) of the desired compound No. 41 at a boiling point of 65° C. to 67° C./0.7 mmHg.
Reaction SMILES: C(C1C=C([CH2+]=NC2C=C[C:15]([O:16]C3C=CN=C(C(NC)=O)C=3)=[CH:14][C:13]=2F)N(C2C=CC=C(CO)C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)CC>O1CCCC1>[C:15]([O:76][CH2:75][C:71]1[CH:72]=[CH:73][CH:74]=[C:69]([N:44]2[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]3[CH:67]=[CH:66][C:54]([O:55][C:56]4[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=4)=[CH:53][C:52]=3[F:68])=[CH:46][C:42]([C:38]([CH3:41])([CH3:39])[CH3:40])=[N:43]2)[CH:70]=1)(=[O:16])[CH2:14][CH3:13]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Agent: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(=O)OCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C(=O)NC)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a room temperature solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (0.20 g, 0.38 mmol) and potassium carbonate (0.26 g, 1.88 mmol) in tetrahydrofuran (5 mL) was added dropwise propionyl chloride (0.05 mL, 0.56 mmol). The reaction mixture was allowed to stir at room temperature overnight. The crude material was concentrated and purified via prep-TLC (CH2Cl2:2M NH3 in MeOH, 97:3) to afford 0.09 g (42%) of the desired product as a white powder. MS m/z 589.1 (M+H)+; Retention time (LC-MS): 3.68 min.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([O:21]CC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[NH3:29]>C(O)(C)C>[C:1]([NH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:19]([NH2:29])=[O:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: NC(=O)c1[nH]c2ccccc2c1NC(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3-Benzamido-2-carboethoxyindole (3.0 g) and phosphorous oxychloride (20 mL) was refluxed for 30 min. The reaction mixture was concentrated in vacuo and the residue was triturated with ether to afford a white solid. This solid was treated with 40 mL of isopropanol which had been previously saturated with ammonia and heated in a sealed tube at 120° C. for 40 min. The reaction mixture was again concentrated in vacuo and the residue was triturated with ether to afford 3-Benzamido-indole-2-carboxamide as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][CH2:18][CH2:19]Cl)[CH:12]=2)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>CS(C)=O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][NH:29][C:26]4[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH:12]=3)[CH:7]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(N)cc1
Reactant: ClCCCOc1ccc2cc(OCCCCl)ccc2c1
Solvent: CS(C)=O
Product: COc1ccc(NCCCOc2ccc3cc(OCCCNc4ccc(OC)cc4)ccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of 2,6-bis(3-chloropropyloxy)naphthalene(1 gm, 0.003 mole) and p-anisidine(1.17 gm, 0.005 mole) was taken in 60 ml dry DMSO. It was refluxed at 140° C. for 12 hrs. The completion of the reaction was checked by TLC. The reaction mixture was poured into distilled water (80 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was further crystallized by benzene hexane to get the desired compound, m.p. 129° C., (yield 1.4 gm, 91%).
Reaction SMILES: C(O[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.CC(C)=[O:15]>>[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:15])=[CH:9][CH:8]=1
Reactant: CC(=O)OC=Cc1ccccc1
Reactant: CC(C)=O
Product: C=Cc1ccc(O)cc1
Temperature: 127.5 °C
Reaction time: 48 h

Procedure:
Acetoxystyrene (75.0 g, 0.463 mol) was placed in a 250 mL round bottom flask and purged with N2. The unimolecular initiating system 1-phenyl-1-(2',2',6',6'-tetramethyl-1'-piperidinyloxy)-ethane (1.21 g, 0.00463 mol) (with no separate free radical initiator used) was then added to the monomer. After addition of the initiator, the polymerization mixture was heated to 125-130° C., under N2, and stirred for 48 hours. During the polymerization the polymer solidified in the reaction vessel. The reaction was then cooled to room temperature and the polymer dissolved in acetone (225 mL), and isolated by precipitation into hexanes (2250 mL). The polymer was then filtered, washed with hexanes and dried in a vacuum oven at 60° C. overnight. Isolated yield was 90% of theory, Mn =8997, Mw /Mn =1.10.
Reaction SMILES: Br[CH2:2][C:3](CBr)=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=[O:40]>>[CH3:2][C:3]([O:40][C:39](=[O:41])[C:38]1[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=1[OH:36])=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:18])[CH3:19])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(CBr)CBr
Agent: CCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Product: CC(=O)OC(=O)c1ccccc1O

Procedure:
(Electrospray MS m/z 540 [MH+ ]) from of N-benzoyl-L-valyl-L-alanyl-L-norleucine bromomethyl ketone and 2-hydroxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:39][CH:40]=2)[CH2:31][C:30]1([CH3:43])[CH3:42])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1(C)C
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 31.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 4-(6-amino-pyridin-3-yl)-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.14 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.525 g, 31.8%). 1H NMR δ (400 MHz, DMSO-d6) 9.96 (s, 1H), 8.91 (s, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.26 (dd, J=3.2, 9.3 Hz, 1H), 6.18 (s, 1H), 5.86 (m, 1H), 3.67 (m, 2H), 3.37 (m, 4H), 2.54 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.71 (m, 2H), 1.53 (m, 2H), 1.39 (s, 9H), 1.33 (s, 6H).
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH:14]([O-])([O-])[O:15][CH2:16][CH3:17]>C(OC(=O)C)(=O)C>[Cl:1][C:2]([F:12])([F:13])[C:3](=[O:11])[C:4](=[CH:14][O:15][CH2:16][CH3:17])[C:5](=[O:10])[C:6]([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOC([O-])[O-]
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C(C)(C)C)C(=O)C(F)(F)Cl
Yield: 43.4 %

Procedure:
12.4 g of 1-chloro-1,1-difluoro-5,5-dimethyl-2,4-hexanedione and 12.4 g of ethyl orthoformate were added to 50 ml of acetic anhydride, and the mixture was refluxed under heating for 2 hours. After the solvent was distilled off under reduced pressure, the residue was subjected to vacuum distillation to obtain 6.8 g of the desired product. (b.p. 105°-107° C./2 mmHg)
Reaction SMILES: CO.[C:3]([O:7]OC(C)(C)C)(C)(C)C.[C:13]([CH:17]=[C:18]([F:20])[F:19])([F:16])([F:15])[F:14]>>[C:13]([CH2:17][C:18]([CH2:3][OH:7])([F:20])[F:19])([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: FC(F)=CC(F)(F)F
Solvent: CO
Product: OCC(F)(F)CC(F)(F)F
Yield: 934.5 %

Procedure:
Under nitrogen, into a quartz tube equipped with a dry-ice condenser was added anhydrous methanol (20 g, 0.62 mol) and di-tertiarybutylperoxide (.79 g, 0.003 mol). The quartz tube was placed in a Rayonet UV photochemical reactor and HFC 1225, CF3CH═CF2 (7 g, 0.05 mol) was added drop-wise via a dry-ice condenser (−78° C.) over a period of ˜30 minutes while being irradiated at 254 nm. After complete addition, the reaction mixture was irradiated for ˜30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was extracted in diethyl ether (˜50 mL), washed with 20 mL aq. Na2SO3 (20%) and brine (10 mL). The ether layer was then concentrated to afford 7 g of the crude material which was distilled under reduced pressure (24-28 mm Hg) to afford CF3CH2CF2CH2OH (4.6 g, mol) as a colorless liquid. Yield=52% based on HFC 1225. Boiling point, 62° C./24-28 mm Hg. GC-MS: m/e 164 (C4H5F5O) for M+;19F and 1H NMR spectra are consistent with the structure. 19 F NMR (CDCl3)δ=−62.4 (3F, tt overlaps), −106.5 (2F, m) ppm; 1H NMR (CDCl3)δ=2.7 (1H, t), 2.9 (2H, m), 3.8 (2H, m) ppm.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:19]1[CH2:20][CH2:21][N:16]([C:2]2[C:7]3[O:8][CH2:9][CH2:10][O:11][C:6]=3[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:17][CH2:18]1
Reactant: CC(=O)Nc1ccc(Br)c2c1OCCO2
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(N2CCOCC2)c2c1OCCO2
Temperature: 130 °C
Yield: 39.1 %

Procedure:
To a solution of N-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (5 g, 18.4 mmol) in toluene (50 mL) was added morpholine (1.9 g, 22 mmol), Pd2(dba)3 (1.68 g, 1.84 mmol), X-Phos (1.75 g, 3.68 mmol) and potassium tert-butoxide (4.1 g, 36.8 mmol) in a sealed tube. The mixture was heated at 130° C. for overnight. After cooled to room temperature, the mixture was filtered and the filtrate was evaporated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to afford the product N-(8-morpholino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (2 g, yield 40%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[O:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: c1ccoc1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccco4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and furane
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[N:11]([CH3:13])[CH3:12])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]([N:10]([C:9]1[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[N:11]([CH3:13])[CH3:12])=[O:23]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N(C(=O)c1ccc(Cl)cc1Cl)c1cc(-c2ccccc2)sc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.11 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 10 mL) and then added 1N aqueous solution of LiOH.H20 (0.67 mL, 0.67 mmol). The reaction mixture was stirred at 60° C. for 2 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by preparative TLC using dichloromethane:methanol (9:1) to obtain 3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid (Compound 72) (0.008 g, 17%). 1H NMR (DMSO, 400 MHz): δ 7.81 (d, 2H), 7.69 (d, 2H), 7.54-7.40 (m, 5H), 2.42 (s, 6H).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([OH:24])=O)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:48]([O:50][C:51](=[O:56])[C@@H:52]([NH:54][CH3:55])[CH3:53])[CH3:49].CN[C@@H](C)C(O)=O.Cl.C(N(CC)CC)C>CN(C)C=O.C(O)C.O1CCOCC1>[CH2:48]([O:50][C:51](=[O:56])[C@@H:52]([N:54]([CH3:55])[C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:24])[CH3:53])[CH3:49]
Reactant: CCOC(=O)[C@H](C)NC
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN[C@@H](C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)N(C)C(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)c2n1CCOC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (100 mg, 0.335 mmol) in dimethylformamide (2.2 ml) was added 1-hydroxybenzotriazole (45 mg, 0.335 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (64 mg, 0.335 mmol). The mixture was stirred for 1 h at 25° C., then (S)-2-methylamino-propionic acid ethyl ester hydrochloride (56 mg, 0.335 mmol) (prepared from (S)-2-methylamino-propionic acid by heating in ethanol and 4 M hydrogen chloride in dioxane for 18 h and evaporation of the solvents) and triethylamine (62 mg, 0.61 mmol) were added and the mixture was stirred at 25° C. overnight. Another portion of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg, 0.067 mmol) and (S)-2-methylamino-propionic acid ethyl ester hydrochloride (12 mg, 0.067 mmol) were added and the mixture was stirred for 1 h. After filtration of the mixture through a short filter cartridge the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 68 mg (51%) (S)-2-{Methyl-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-amino}-propionic acid ethyl ester. LC/MS (method 2): Rt=1.11 min; m/z=442.3 (M+H+). 1H-NMR: δ (ppm)=8.46 (1H, t), 8.21 (1H, d), 7.35-7.36 (3H, m), 7.30 (2H, t), 7.21 (1H, t), 4.91 (2H, dd), 4.82 (1H, q), 4.19 (2H, t), 4.11 (2H, q), 3.90-3.92 (4H, m), 1.71-1.83 (2H, m), 1.21 (3H, t), 0.88 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:19]([O:11][CH2:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([F:1])[CH:7]=1)[CH3:12])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(CCO)c1ccc(-c2ccccc2)c(F)c1
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CCOC(=O)c1ccccc1)c1ccc(-c2ccccc2)c(F)c1

Procedure:
Using a procedure analogous to that described in Example 3, 5.85 gm (67% of theory) of the ester of the formula ##EQU28## having a boiling point of 181°-185°C at 0.05 mm Hg were obtained by refluxing a mixture consisting of 6.11 gm (0.025 mol) of 3-(2-fluoro-4-biphenylyl)-1-butanol, 6.20 gm (0.051 mol) of benzoic acid, 0.5 gm of p-toluene-sulfonic acid and 40 ml of toluene until no more water separated out.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[S:51]([CH3:54])(=[O:53])=[O:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[S:51]([CH3:54])(=[O:53])=[O:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CS(=O)(=O)c1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3S(C)(=O)=O)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS (m/e): 451.3 (MH+).