Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[O:13][C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(OCC)(=O)C>[C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[O:30])=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccncc2-c2ccccc2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccncc2-c2ccccc2)cc1
Reaction time: 0.67 h

Procedure:
Ethyl acetate (10 ml) was added to 4-(3-phenylpyridin-4-yl)oxyaniline (84 mg, 0.32 mM), and then parafluorophenyl isocyanate (0.54 ml, 4.7 mM) was added while stirring, which was continued for 40 minutes. After adding NH type silica gel to the reaction solution, the solvent was distilled off under reduced pressure to adsorb the reaction product onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, for column purification (chloroform:methanol=10:1). After adding ethyl acetate and n-hexane to the obtained residue, the solvent was distilled off under reduced pressure to obtain the target compound (82 mg) as a light yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:4][C:3]=1[F:13].[BH4-].[Li+].C[Si](Cl)(C)C.CO>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[F:13]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 78 h
Yield: 115.9 %

Procedure:
1-Chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (I-33a: 1.1 g, 4.97 mmol) in dry THF (8 mL) was added to a stirred solution of lithium borohydride (433 mg, 19.90 mmol) and trimethylsilyl chloride (5 mL, 39.66 mmol) in dry THF (8 mL) at 0° C. The resulting mixture was stirred at room temperature for 78 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was cooled to 0° C., quenched with methanol and concentrated under reduced pressure to afford 1 g of the product (100% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:23][NH2:24])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)C=O)([O-:27])=[O:26].[C:36](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][CH:2]([CH2:23][NH:24][CH2:36][C:29]1[CH:30]=[CH:33][CH:34]=[CH:35][C:28]=1[N+:25]([O-:27])=[O:26])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CN
Reactant: CC(=O)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CNCc1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of (±)-2-Methyl-3-amino-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (94 mg), 3-nitrobenzaldehyde (40 mg), glacial acetic acid (90 μl), and sodium triacetoxyborohydride (78 mg) in dichloromethane (5 ml) was stirred overnight. The reaction mixture was partitioned between aq. K2CO3 (1N, 10 mL) and ethyl acetate (5 ml). The aqueous was washed with EtOAc (5 mL×2). Organic layers were combined, washed with brine, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica (20-50% ethyl acetate in hexane) and yielded (±)-2-Methyl-3-((2-nitro)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide as a resin: MS (m+1)=490.3.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 80 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: C[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]([OH:16])=O)[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][CH:57]([CH3:60])[CH2:58][OH:59]>CN(C=O)C.O>[OH:59][CH2:58][CH:57]([NH:56][C:14]([C:4]1[C:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:2][N:7]=[N:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[CH3:60]
Reactant: CC(N)CO
Reactant: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CO)NC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
To a solution of methyl 3,5-diphenylpyrridazine-4-carboxylic acid (compound 6) (250 mg, 0.90 mmol) in DMF (3 mL), DIPEA (0.47 mL, 2.71 mmol), HATU (516 mg, 1.35 mmol) were sequentially added and stirred at rt. After 15 min. 2-amino-1-propanol (203 mg, 2.71 mmol) was added and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). Combined organic extract was washed with water (2×10 mL), brine (1×10 mL) and dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the crude product N-(1-hydroxy propan-2-yl)-3,5-diphenylpyridazine-4-carboxamide (160 mg) as an off white solid.
Reaction SMILES: O[CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=2[N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[O:10])[C@@H:7]([CH3:23])[CH2:6][CH2:5][O:4]1.C(C=P(CCCC)(CCCC)CCCC)#N.[F:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:48]=[N:49][NH:50][CH:51]=2)=[N:45][CH:46]=1>C1(C)C=CC=CC=1>[F:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:51]=[N:50][N:49]([CH2:2][C@H:3]3[N:8]([C:9]([C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=4[N:18]4[N:19]=[CH:20][CH:21]=[N:22]4)=[O:10])[C@@H:7]([CH3:23])[CH2:6][CH2:5][O:4]3)[CH:48]=2)=[N:45][CH:46]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2[C@H](CO)OCC[C@@H]2C)c1
Reactant: Fc1ccc(-c2cn[nH]c2)nc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2[C@H](Cn3cc(-c4ccc(F)cn4)cn3)OCC[C@@H]2C)c1
Temperature: 100 °C

Procedure:
To a solution of [(2S,4S)-2-(hydroxymethyl)-4-methyl-1,3-oxazinan-3-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone obtained in Reference Example 17 (0.070 g, 0.22 mmol) in toluene (1 mL), 5-fluoro-2-(1H-pyrazol-4-yl)pyridine obtained in Reference Example 11 (0.040 g, 0.24 mmol) and cyanomethylene tributylphosphorane (0.087 mL, 0.33 mmol) were added, and the resulting mixture was stirred with heating for 3 hours at 100° C. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (KP-NH 12 g, hexane/EtOAc=80/20 to 0/100) (HP-Sil 10 g, hexane/EtOAc=80/20 to 0/100) to obtain the title compound (0.11 g) (colorless oil).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:27])([F:26])[F:25])[CH2:10]1)C1C=CC=CC=1.O>[Pd].CC(O)C>[ClH:1].[NH:9]1[CH2:14][CH2:13][O:12][C@@H:11]([C@:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([OH:28])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][C:24]([F:27])([F:26])[F:25])[CH2:10]1
Reactant: OC(Cc1ccccc1OC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: O[C@@](Cc1ccccc1OC(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Alternatively, the following method may be used. In a glass-lined nitrogen purged hydrogenator are charged 1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol hydrochloride (150 g, 303.7 mmol), demineralized water (352 mL), i-PrOH (375 mL) and 5% Pd/C (30 g, 50% water, Johnson & Matthey type 440). The heterogeneous reaction mixture was then purged 5 times with 25 psi nitrogen then purged 5 times with 50 psi hydrogen, and the hydrogenation was performed at RT. The initial Tmass was 22° C. and the maximum Tmass during the hydrogenation was 23° C. The reactor was stirred vigorously. In-process analysis after 2 hours indicated complete hydrogenolysis. The hydrogenation was stopped after 3 hours. The nitrogen purged reaction mixture was then filtered at RT through an hyflo filter (56 g), impregnated beforehand with 75 mL of a 50/50 v/v isopropanol/water mixture and washed with 300 mL of a 50/50 v/v isopropanol/water mixture. The filtrates were stored overnight at RT. The filtrates were concentrated at 40-50° C. under reduced pressure (typical 622 g distilled). The reaction mixture was cooled to RT and post-agitated. After 3 hours, 1 mL of the solution was taken and cooled to 0° C. to initiate crystallization. These seeds were added to the reaction mixture and precipitation was observed within a few minutes. The mixture was post-agitated at RT for 2 hours. The crystals were filtered and rinsed with H20 (30 mL). Then, the precipitate was dried under reduced pressure (400 mmHg) with a nitrogen flow (0.1 bar) for 4 hours affording the title compound as the hydrate polymorph (103.5 g, 81% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[C:14]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:19]1[S:20][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)s1

Procedure:
Followed the two step synthesis shown in Scheme 1 starting with 2-chloro-6-methoxyquinoline and 5-cyanothiophen-2-ylboronic acid, with minor variations: the base used in step 1 was sodium carbonate and the solvent was DME (dimethoxyethane)/water. In step 2, after quenching w/ ice water, a standard ethyl acetate extraction was preformed followed by purification by prep-TLC (PE:EA=1:1).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:25][Br:26]>C1(C)C=CC=CC=1>[Br-:26].[CH3:33][O:32][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:29]=1[O:30][CH3:31])[CH2:25][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(CBr)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Product: [Br-]
Reaction time: 24 h

Procedure:
A solution of triphenylphosphine (4.2 g) in toluene (10 mL) was added to a stirred solution of 3,4,5-trimethoxybenzyl bromide (4.0 g) in toluene (15 mL) and stirring was continued for 24 hours. The phosphonium bromide that separated (8.0 g, 99%) was collected and dried under vacuum, mp 223-4 (lit 222°-23° C.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:45]2[N:46]=[C:47]([NH:50][C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[S:48][CH:49]=2)\[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[C:22]([CH2:25][I:26])[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:70]1([P:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>C1C=CC=CC=1.CCCCCC>[I-:26].[C:1]([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:45]2[N:46]=[C:47]([NH:50][C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[S:48][CH:49]=2)\[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[C:22]([CH2:25][P+:76]([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)([C:83]4[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=4)[C:70]4[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-5', 6.4 g, 6 mmoles) and triphenylphosphine (2.4 g, 9 mmoles) in benzene (120 ml) was stirred at room temperature for 2 hours and diluted with n-hexane (ca. 500 ml). The resulting precipitate was collected by filtration to afford 7.5 g (94%) of the title compound VIII-B 5'.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.O[CH:22]([C:28](C)=C)[C:23](OCC)=O.C(OCC)(=[O:35])C=CC.Cl>C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:35])[C:17](=[C:22]([CH3:28])[CH3:23])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC=CC(=O)OCC
Reactant: C=C(C)C(O)C(=O)OCC
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 57.9 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-flourophenyl)carbamate (3.01 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (4.32 g, 30 mmol), ferric chloride (162 mg, 1.0 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (100 cc) equipped with an air condenser tube (20 cm), and the reaction was conducted at 210° C. for 3.5 hours under such a reduced pressure that the ethyl butenoate was refluxed below the middle of the air condenser tube. After the reaction solution was cooled to room temperature, toluene (30 mL) was added, and the reaction solution was washed with 1N sodium hydroxide (20 mL×2) and then 1N hydrochloric acid (20 mL×2). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. Methanol (3.5 mL) acidified with hydrochloric acid was added to the resulting oily crude product to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, washed with a 4:1 mixed solvent containing of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (2.05 g, yield 57.9%).
Reaction SMILES: C1(C)C=CC=CC=1.C(C1C=CC=CC=1O)C=C.C[SiH](C)O[SiH](C)C.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][CH2:34][Si:35]([CH3:51])([CH3:50])[O:36][Si:37](CCCC1C=CC=CC=1O)([CH3:39])[CH3:38]>C(O)(CC)(C)C>[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][CH2:34][Si:35]([CH3:51])([CH3:50])[O:36][SiH:37]([CH3:39])[CH3:38]
Reactant: C[Si](C)(CCCc1ccccc1O)O[Si](C)(C)CCCc1ccccc1O
Agent: C=CCc1ccccc1O
Agent: C[SiH](C)O[SiH](C)C
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Product: C[SiH](C)O[Si](C)(C)CCCc1ccccc1O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a 85 ml toluene solution containing 67.1 g (0.5 mole) of 2-allylphenol and 0.4 g of a 5% solution of H2PtCl6 in t-amyl alcohol is added a solution consisting of 15 ml of toluene and 38.8 g (0.25 mole) of 1,1,3,3-tetramethyldisiloxane at 75° C. The addition is complete in 1 hour. The mixture is heated at 85° C. for 1 hour and then at 105° C. for 3 hours. After washing successively three times with 100 ml portions of water, 101 g of the 2:1 molar adduct, 1,3-bis-(3-(2-hydroxylphenyl)-propyl)-1,1,3,3-tetramethyldisiloxane (>92% pure by gel chromatography, GC) having a light straw color is obtained after stripping off solvent. The structure of the product 1,3-bis-(3-(2-hydroxylphenyl)-propyl)-1,1,3,3-tetramethyldisiloxane is confirmed by 1H NMR and IR (neat).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].Cl.[CH2:9]([C:16]([NH2:18])=[NH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.ClCCCl>[CH3:5][O:4][C:2]([NH:18][C:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[NH:17])=[O:3]
Reactant: N=C(N)Cc1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)NC(=N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
137.2 parts of methyl chloroformate and a solution of 162.7 parts of potassium hydroxide in 180 parts of water are added via two inlets to a mixture of 246 parts of benzylmethanamidine hydrochloride in 530 parts of 1,2-dichloroethane and 85 parts of water, at from 10° to 15° C., in the course of 35 minutes. The mixture is stirred at 25° C. for 20 minutes, the organic phase is separated off and the aqueous phase is extracted twice more with 1,2- dichloroethane. The organic extracts are concentrated to give 259.8 parts (93% of theory) of N-methoxycarbonylbenzylmethanamidine of nD25 1.5247.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].Br[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH2:14][CH2:15][OH:16])[C:5]2=[O:12]
Reactant: OCCBr
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(Br)ccc2ncn1CCO

Procedure:
6-Bromoquinazolin-4(3H)-one Compound 178-A (1.0 g), 2-bromoethanol (1.1 g), and potassium carbonate (610 mg) were heated in DMA (10 mL) at 80° C. for 16 h. Reaction was extracted with water and dichloromethane (3 times), combined organic layers washed with brine, over sodium sulphate and concentrated. Residue was triturated with acetonitrile to yield 6-bromo-3-(2-hydroxyethyl)quinazolin-4(3H)-one Compound 178-B (810 mg) as a white solid. MS m/z (ESI)=268.9 (base peak, 79Br−M+H+); 270.9 (81Br−M+H+); 290.9 (79Br−M+Na+); 292.9 (81Br−M+Na+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].O.[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C#N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of the product from Example 26A (6.1 g, 31.9 mmol) and lithium hydroxide monohydrate (5.36 g, 128 mmol) in THF (100 mL) and H2O (50 mL) was stirred at rt for 3 hrs. The reaction pH was adjusted to 3 with 3N HCl, and the mixture was extracted twice with isopropanol/CH2Cl2 (1:3). The organics were combined, dried (MgSO4), filtered and concentrated to afford 5.6 g (99%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 4.15 (s, 3 H) 7.17 (d, J=8.85 Hz, 1 H) 7.86 (dd, J=8.85, 2.44 Hz, 1 H) 8.47 (d, J=2.14 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O.[I-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: BrCc1cccc(Br)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Brc1cccc(Cn2cncn2)c1
Temperature: 55 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a solution of 3-bromobenzylbromide (20.0 g, 80.0 mmol) in acetone (300 mL) was added 1,2,4-triazole (10.8 g, 120 mmol), potassium carbonate (11.0 g, 80.0 mmol) and potassium iodide (0.790 g, 4.72 mmol). The resulting white suspension was heated to 55° C. with vigorous stirring for 16 h. The yellow reaction mixture was cooled and ethyl acetate (100 mL) added. This was then washed with distilled water (100 mL×2), 1M NaOH(aq) (100 mL×2) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and solvent removed in vacuo to leave clear yellow oil. The crude product was purified by column chromatography (ethyl acetate) to give the title compound as a yellow crystalline solid (12.4 g, 65%),
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[C:31]1([CH2:41][NH2:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:42][CH2:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (3.0 g, 6.86 mmol) (Preparation 10), 1-naphthalenemethylamine (1.2 g, 7.63 mmol), and triethylamine (2.8 g, 27.72 mmol) in acetonitrile (30 ml) was left to stand at room temperature for 2 hours during which time a fine precipitate slowly formed. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (150 ml) and water (50 ml). The organic phase was separated and the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 by volume) to give a product which was azeotroped with dichloromethane to afford the title compound as a foam (3.6 g).