Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].O>C(O)C>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][CH:38]=2)[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH2:27][NH:9][CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccccc1C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Reactant: NC1CCCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(C(c3ccc(OCc4ccccc4)cc3)c3ccccc3CNC3CCCCCCC3)cc2)cc1
Yield: 65.5 %

Procedure:
In 50 ml of ethanol was dissolved 3 g of cyclooctylamine. To the solution was added 11.41 g of 2-[bis-(4-benzyloxyphenyl)methyl]benzaldehyde obtained by Reference Example 8, and the mixture was heated under reflux for 2 hours. Thereafter, 1.78 g of sodium borohydride was added thereto, and the mixture was heated under reflux for 2 hours. The solvent was evaporated-under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with ether, and the organic layer was separated. The aqueous layer was extracted with ether, and then the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized to afford 9.19 g of the desired product (Compound 82).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[N:16][CH:15]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[N:13]=1.O>CS(C)=O>[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[CH:17]=[N:16][CH:15]=[C:14]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[N:13]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(C)n(-c2cncc(Cl)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)n(-c2cncc(Nc3ccc(Cl)cc3)n2)n1
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Sodium hydride (60% in mineral oil, 161 mg, 4.03 mmol) was added to a suspension of 4-chloroaniline (489 mg, 3.83 mmol) in dimethylsulfoxide (10 mL). The mixture was stirred at 130° C. for 5 minutes. 2-Chloro-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazine was added and the resulting mixture was stirred at 130° C. for 30 minutes. Cooling, followed by addition of water gave a brown precipitate. The brown solid was collected by filtration, re-dissolved in ethyl acetate, washed with brine, dried over sodium sulphate, filtrated and evaporated. The crude product was purified by flash chromatography to give (4-chloro-phenyl)-[6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-amine (318 mg, 55%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: N#Cc1cccc(-c2ccc(C=O)cc2Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(-c2ccc(CO)cc2Cl)c1
Reaction time: 1 h

Procedure:
2′-Chloro-4′-formyl-biphenyl-3-carbonitrile (I-6b: 6.0 g) was dissolved in 150 mL of methanol before sodium borohydride (3.4 g) was added gradually. After 1 hour, the reaction mixture was concentrated under reduced pressure, the resulting residue was taken up in 100 mL of ethyl acetated and washed twice with 20 mL of water. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (I-6c).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([CH:11]([CH3:14])[C:12]#[N:13])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc(C(C)C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(C)C#N)cc1Br
Reaction time: 0.5 h

Procedure:
Bromine (21.4 ml) is added dropwise over a period of 1 hour to a stirred solution of 4-methoxyphenylpropionitrile (67.5 g) and sodium acetate (68.4 g) in glacial acetic acid (420 ml). The reaction mixture is stirred for an additional 30 minutes and partitioned between water and ether. The ether layer is washed with sodium carbonate solution, 10% aqueous NaOH, saturated salt, dried over Na2SO4 and filtered. The filtrate is evaporated in vacuo yielding the desired product, B.P. 155°-158° C. (4 mm).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH:39]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:39]1[CH:43]=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:41]=[N:40]1
Reactant: OB(O)c1cn[nH]c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cn[nH]c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 39.5 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (57 mg, 0.10 mmol) was treated with (1H-pyrazol-4-yl)boronic acid (64 mg, 0.58 mmol), sodium carbonate (65 mg, 0.61 mmols) and bis(triphenylphosphine)palladium(II) dichloride (33 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 23 mg (41% yield) of the title compound. Purity 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]2[N:18]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1F
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)cc3F)nc12
Yield: 22.2 %

Procedure:
Reaction of 1-(2,4-difluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (252 mg, 1.0 mmol), prepared from commercially available 2,4-difluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (72 mg, 22%). MS (ISP) 325.0 [(M+H)+]; mp 149° C.
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]C)=O)=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[N:3][CH:2]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][C:17]=1[CH3:24]>CN(C=O)C>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:7]([C:6]2[N:1]=[CH:2][N:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=2)=[O:9])=[CH:18][C:17]=1[CH3:24]
Reactant: COC(=O)c1cc(C(=O)OC)ncn1
Reactant: Cc1cc(CN)ccc1F
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)NCc2ccc(F)c(C)c2)ncn1
Temperature: 60 °C
Reaction time: 48 h
Yield: 64.1 %

Procedure:
8.81 g (0.045 mol) of dimethyl pyrimidine-4,6-dicarboxylate were dissolved in 200 ml of DMF, after which 6.25 g (0.045 mol) of 4-fluoro-3-methylbenzylamine were added and the mixture was stirred at 60° C. for 48 hours (h). The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed with a saturated solution of sodium hydrogen carbonate and 0.5 N HCl and then dried (MgSO4). After filtering, and evaporating the solvent in vacuo, the residue was stirred up in isopropanol. This resulted in 8.75 g of product, which was subjected to further reaction without any further purification.
Reaction SMILES: [Si]([N:8]1[CH:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10][C:9]1=[O:22])(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH2:31]([O:34][C:35]([N:37]1[CH2:41][C@@H:40]([S:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][C@H:38]1[CH2:62]I)=[O:36])[CH:32]=[CH2:33]>>[CH2:31]([O:34][C:35]([N:37]1[CH2:41][C@@H:40]([S:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][C@H:38]1[CH2:62][CH:10]1[CH2:11][C@@H:12]([CH2:13][OH:14])[NH:8][C:9]1=[O:22])=[O:36])[CH:32]=[CH2:33]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1C[C@@H](CO)NC1=O
Yield: 20.4 %

Procedure:
The same procedure as in Reference Example 22-1 was carried out by using N-tert-butyldimethylsilyl-5-tert-butyldimethylsiloxymethyl-2-oxopyrrolidine (10.67 g, 31.6 mmol), lithium diisopropylamide (2.1M tetrahydrofuran solution, 15.1 ml, 31.6 mmol) and (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (10 g, 17.6 mmol) to obtain (2R,4S)-N-allyloxycarbonyl-2-[(5S)-5-hydroxymethyl-2-oxopyrrolidin-3-ylmethyl]-4-tritylthiopyrrolidine (2 g, yield: 21%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[CH:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)=[CH:24][CH:25]=1>>[CH2:26]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:31][CH:32]=1)[C:23]1[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: Oc1ccc(Cc2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 4-hydroxydiphenylmethane in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H24O4[M−H]−: 399.
Reaction SMILES: [CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:28][CH:29]=3)[C:8](=[O:22])[N:9]([CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[OH:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1cc2c(=O)n(CC(O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.5 g) in CHCl3-methanol (1:1, 30 mL) was added NaBH4 (0.039 g) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, water was added and the mixture was adjusted to pH 5-6 with 1N hydrochloric acid and water, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object compound (0.50 g, 100%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9](F)[C:8]=2[F:16])[CH2:6][CH2:5]1.O>CO>[CH:4]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:2][CH3:1])[C:8]=2[F:16])[CH2:6][CH2:5]1
Reactant: C[O-]
Reactant: O=Cc1ccc(C2CC2)c(F)c1F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C=O)ccc(C2CC2)c1F
Reaction time: 15 h
Yield: 91.6 %

Procedure:
Sodium methoxide (28% methanol solution, 3.43 g) was added at room temperature to a methanol (100 mL) solution of 4-cyclopropyl-2,3-difluorobenzaldehyde (2.16 g), and the mixture was stirred at 70 C for 15 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and methanol was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.11 g)
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]1(=[N:30]O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.[OH-:32].[Na+]>>[NH:30]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:29]=2[CH2:28][CH2:27][CH2:26][C:25]1=[O:32]
Reactant: ON=C1CCCc2ccccc21
Reactant: [OH-]
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: O=C1CCCc2ccccc2N1
Temperature: 90 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To 10 L of methanesulfonic acid in a 22 L 3-neck flask equipped with an overhead stirrer, a temperature probe, nitrogen inlet and reflux condenser, was added 2.6 Kg (18.61 mol) of phosphorus pentoxide. An additional 1.6 L of methanesulfonic acid was used to wash all the phosphorus pentoxide into the vessel. The mixture was heated at 90° C. for 2.5 hours then cooled to 50° C. using an ice bath and treated with 2.00 Kg (12.41 mol) of 1-tetralone oxime in several portions over 15 minutes. The mixture was heated at 63° C. for 10 minutes then slowly heated to 80° C. and kept at 80° C. for 3 hours. The reaction mixture was pumped into 70 L of ice then treated slowly with 11.25 L of 50% aqueous sodium hydroxide over 90 minutes at such a rate so as to maintain the temperature below 28° C. The mixture was filtered and 4 L of the filtrate was used to rinse the vessel. The wet cake (pink) was washed with 8 L of water then suction dried for 45 minutes and transferred to two trays and dried under vacuum at 40° C. for 2 days to give 1.9 Kg (11.79 mol, 95%) of product. 1H MNR (250 MHz,CDCl3): 2.24 (m, 2H), 2.38 (t,6 Hz, 2H), 2.82 (t, 6 Hz, 2H), 7.03 (d, 8 Hz, 1H), 7,13 (m,1H), 7.24 (m, 2H), 8,63 (br s 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[C:5]=1[CH:14]=[O:15].CN(C)C=O.Cl[C:22]1[S:23][C:24]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:27])[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:2][O:3][C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][N:9]([C:22]3[S:23][C:24]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])=[C:25]([CH3:27])[N:26]=3)[CH2:8][CH2:7][C:6]=2[C:5]=1[CH:14]=[O:15]
Reactant: Cc1nc(Cl)sc1C(=O)N1CCOCC1
Reactant: COc1ccc2c(c1C=O)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1C=O)CCN(c1nc(C)c(C(=O)N3CCOCC3)s1)C2
Temperature: 0.11999999731779099 °C
Reaction time: 3.5 h
Yield: 25.6 %

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde hydrochloride (82 mg, 0.36 mmol), anhydrous dimethylformamide (5 mL), (2-chloro-4-methyl-thiazol-5-yl)-morpholin-4-yl-methanone (89 mg, 0.36 mmol) and freshly dried potassium carbonate (149 mg, 1.08 mmol) was stirred under argon at 0.120° C. for 3.5 h and then at 150° C. for 1 h. Water (20 mL) was added and the separated solid product was filtered off. The filtrate was extracted with diethyl ether (5×10 mL) and the combined extracts were washed with water (2×10 mL), dried and concentrated. The residue and the above solid product were combined and triturated repeatedly with diisopropyl ether. In this manner the title compound (37 mg, 0.092 mmol, 26%) was obtained as a beige powder.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C=O)C.[Na+].[I-]>[CH2:8]([O:7][CH2:6][C@@H:4]1[CH2:3][O:5]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC1CO1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COC[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A slurry of NaH (267 g) and NaI (26.5 g) in DMF (3000 mL) was cooled to between −15° C. and −10° C. with ice-brine mixture. A solution of glycidol (480 g) in DMF (1000 mL) was added with stirring for 10 minutes. BnCl (745.5 g) in DMF (800 mL) was added (slightly exothermic) and the reaction was warmed to room temperature followed by stirring for approximately 16 hours. The solution was stirred for a further time period until HPLC analysis showed less than 1% of BnCl remained. The reaction was cooled to −5° C. and water (4 L) was added. MBTE (5 L) was added with stirring for 30 minutes. The organic and aqueous layers were separated and two additions of MBTE (5 L; 3.5 L) were used to extract the aqueous layer. The combined organic layer was washed with brine (1.8 L (×2)) and dried over Na2SO4 for 1 hour. The organic layer was concentrated to dryness, distilled under vacuum (5 mm Hg, 85° C.) to give the product as a yellow liquid (760 g). 1H NMR (CDCl3, 400 MHz): δ 7.27-7.37 (m, 5H), 4.51 (s, 2H), 3.74 (dd, 1H), 3.29 (dd, 1H), 3.14 (m, 1H), 2.72 (dd, 1H), 2.55 (dd, 1H).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]1C(=O)C)C.Cl.O1CCOCC1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CC(O)=O.[OH-].[Na+]>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:6]2[CH2:7][CH2:8][C@@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:5]2[C:4]([OH:3])=[O:19])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@@H]1[C@H](c2ccccc2)CCN1C(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2CC[C@@H](c3ccccc3)[C@H]2C(=O)O)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
N-Acetyl-cis-3-phenylproline ethyl ester (614 mg, 2.35 mmol) (prepared via the method of Chung, et al., J. Org. Chem.55: 270-275 (1990)) was dissolved in HOAc (4 mL) and 6N HCl (12 mL) and heated at reflux for 18 hr. The mixture was cooled to room temperature and the volatiles were evaporated in vacuo to give a white solid. The solid was dissolved in 1N NaOH (15 mL) and dioxane was added (10 mL), followed by 4-toluene-sulfonyl chloride (458 mg, 2.40 mmol). The mixture was stirred at room temp for 18 hr before addition of 6N HCl to bring the pH<4. The mixture was extracted with Et2O (3×40 mL) and the extracts were dried (MgSO4), filtered, and evaporated in vacuo to give N-(toluene-4-sulfonyl)-cis-3-phenylproline as a white solid (765 mg, 94%).
Reaction SMILES: [C:1](Br)(=[O:7])[CH2:2]CCCC.[CH3:9][N:10]([CH2:14][C:15]([O-:17])=[O:16])[C:11]([NH2:13])=[NH:12].[Na+]>>[CH3:9][N:10]([CH2:14][C:15]([O:17][C:1](=[O:7])[CH2:2][N:10]([CH3:9])[C:11]([NH2:13])=[NH:12])=[O:16])[C:11]([NH2:13])=[NH:12]
Reactant: CN(CC(=O)[O-])C(=N)N
Reactant: CCCCCC(=O)Br
Agent: [Na+]
Product: CN(CC(=O)OC(=O)CN(C)C(=N)N)C(=N)N
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81 g (60 mmol) of the prepared hexanoyl bromide, and side arm water condenser fixed with a dry receiving flask, is placed 13.18 g (72 mmol) of sodium 2-(1-methylguanidino)acetate. The round bottomed flask is placed in an ice bath and the hexanoyl bromide is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield hexanoic 2-(1-methylguanidino)acetic anhydride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]1[O:14][CH:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[OH:14][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: c1ccc(C2CO2)cc1
Reactant: COCCN
Product: COCCNCC(O)c1ccccc1

Procedure:
To 157 g of refluxing 2-methoxyethylamine is added dropwise 25 g styrene oxide during a period of 15 minutes. After addition of the amine, the mixture is allowed to reflux for another two hours.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])=[N:7][N:6]=[CH:5][C:4]=2[CH:3]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[CH:34]1([NH:37][C:38](=[O:55])[C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:40]=2)[CH2:36][CH2:35]1>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>[CH:34]1([NH:37][C:38](=[O:55])[C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[C:41]([C:2]3[C:11](=[O:12])[N:10]([CH3:13])[C:9]4[C:8]([C:14]5[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=5[F:21])=[N:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[CH:40]=2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)cc2cnnc(-c3ccc(F)cc3F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(-c3ccc(F)cc3F)c2n(C)c1=O
Temperature: 100 °C

Procedure:
To a suspension of 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one (8) (80.0 mg, 0.227 mmol) in 3:1 1,4-dioxane: 1 M aq Na2CO3 (3.2 mL) was added N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (82.1 mg, 0.273 mmol) and tetrakis(triphenylphosphine)palladium (0) (21.0 mg, 0.0182 mmol). The reaction mixture was stirred and heated in a microwave at 100° C. for 55 min and then cooled to room temperature. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic extract was washed with 2 M Na2CO3, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography [eluting with a gradient of 40-50% B in A where the eluents were: A=CH2Cl2; B=4% MeOH in EtOAc] to give N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazin-3-yl)-4-methylbenzamide as a white solid. MS (ESI, pos. ion) m/z: 447 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.52-0.60 (m, 2H), 0.64-0.73 (m, 2H), 2.21 (s, 3H), 2.85 (td, J=3.9, 7.3 Hz, 1H), 3.16 (s, 3H), 7.32-7.42 (m, 2H), 7.45-7.54 (m, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.79-7.91 (m, 2H), 8.19 (s, 1H), 8.41 (d, J=3.9 Hz, 1H), 9.45 (s, 1H).