Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29]C(C)(C)C)=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].Cl>ClCCl>[C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:25])([CH3:26])[C@@H:20]2[C:27]([OH:29])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Through a solution of 0.250 g (0.503 mmol) of tert-butyl(3 S)4-[(4-{[4-(acetyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate in 10 mL of dichloromethane was bubbled hydrogen chloride gas for 10 minutes. The reaction was then stoppered and let sit overnight at room temperature The solvent was evaporated to give 0.192 g of (3S)-4-[(4-([4-(acetyloxy)-2-butynyl]oxy)phenyl)sulfonyl]-2,2 dimethyl-3-thiomorpholine carboxylic acid as a colorless oil. Electrospray Mass Spec 440.1 (M−H)−
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21]C(=O)OC(C)(C)C)[CH2:11][C:10]1=[O:29].CO.C(Cl)Cl>C(Cl)Cl>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[CH:12]1[CH2:13][CH2:14][N:9]([CH3:8])[C:10](=[O:29])[CH2:11]1
Reactant: CN1CCC(c2ccncc2NC(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccncc2N)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
TFA (0.75 mL, 9.735 mmol) was added to a solution of tert-butyl N-[4-(1-methyl-2-oxo-4-piperidyl)-3-pyridyl]carbamate (74 mg, 0.2423 mmol) in DCM (2 mL) and was stirred at ambient temperature for 2 hours. The reaction mixture was adsorbed onto a pre-wetted (methanol/DCM (1:1), 2 mL) SCX-2 cartridge (2 g) and flushed with DCM/methanol (1:1, 20 mL) and then the basic components eluted with 2 M ammonia in methanol (20 mL). The basic eluent was evaporated to dryness to afford 4-(3-aminopyridin-4-yl)-1-methylpiperidin-2-one as a pale yellow oil (50 mg, 97%). MS (ES+) 206.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[CH2:29]([C:31]1[N:35]=[C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[O:33][N:32]=1)[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[O:33][N:32]=[C:31]([CH2:29][CH3:30])[N:35]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (99.4 mg; compound C10), 1-(3-Ethyl-[1,2,4]oxadiazol-5-ylmethyl)-6-phenyl-3-piperidin-4-yl-1H-thieno[3,2-d]pyrimidine-2,4-dione (109 mg; compound B52) and HOBT (38 mg) in DCM (2.5 ml) is added EDCI (48.9 mg). The mixture is stirred for 2.5 h at RT. EtOAc (25 ml) is added and the mixture is extracted with 1 M aqueous hydrochloride solution (5 ml) (three times). The combined aqueous phases are washed with EtOAc (15 ml) and subsequently the combined organic phases are washed with water (5 ml) (three times) and afterwards with saturated solution of sodium bicarbonate (10 ml) (three times). The organic phase is dried over magnesium sulfate, concentrated in vacuo and the resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: EtOAc/cyclohexane=0/100 to 20/80 (v/v)] to give the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[H-].[O-2:10].[Al+3].[O-2].[O-2].[Al+3]>C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:5][CH2:6][CH:7]1[O:10][CH2:8]1)[CH:2]1[O:4][CH2:3]1
Reactant: C=CCOCC1CO1
Reactant: [O-2]
Agent: O=[Pt]=O
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Product: C(OCC1CO1)C1CO1
Temperature: 90 °C
Yield: 87.2 %

Procedure:
Allyl glycidyl ether (13.2 mL, 0.111 mol) was added to HMS-501 (10.0 g, 0.0741 mol) in toluene. A catalytic amount of PtO2 was added, and the mixture was heated at 90° C., overnight. An NMR spectrum taken the following day showed there to be substantially no remaining hydride (peak at approx. 4.7 ppm). The reaction mixture was then cooled and passed through a bed of aluminum oxide layered on top of a fitted glass filter. The frit was washed with additional toluene. The eluent was collected in a round-bottom flask. The solvent and residual allyl glycidyl ether were then removed in vacuo at 50° C., to yield the epoxy-PDMS as a thick clear liquid (16.09 g, 87.2%).
Reaction SMILES: CP(C)C.O1CCCC1.[CH2:10]([O:12][C:13]([C@:15]1([N:37]=[N+]=[N-])[C@H:20]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:14])[CH3:11].C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)C>[CH2:10]([O:12][C:13]([C@:15]1([NH2:37])[C@H:20]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:14])[CH3:11]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](SCc3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: CP(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
7.7 mL of a solution of 1M trimethylphosphine/tetrahydrofuran was added to 3.35 g of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 100 mL of tetrahydrofuran and 10 mL of water, and the mixture was stirred for 1 hour at room temperature. The mixture was diluted with 200 mL of diethyl ether, and after 50 mL of a saturated aqueous solution of sodium hydrogen carbonate was added thereto, the mixture was stirred for 1.5 hours at room temperature. After separation, the organic layers were washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was diluted with chloroform, and then silica gel (Wako gel C200 (made by Wako Pharmaceutical Industries Ltd.)) was added thereto. The mixture was concentrated under reduced pressure, left to stand for 18 hours at room temperature, and then purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=2:1), thereby yielding 2.78 g of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[O:15][C:14]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:13][CH:12]=1>C1COCC1>[OH:19][N:18]([CH:16]([C:14]1[O:15][C:11]([CH3:10])=[CH:12][CH:13]=1)[CH3:17])[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: Cc1ccc(C(C)NO)o1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C(C)N(O)C(=O)Nc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of phenyl isocyanate (0.87 mL, 8.0 mmol) in 10 mL THF was added N-(1-(5-methyl-fur-2-yl)ethyl) hydroxylamine (0.50 g, 4.0 mmol) in 3 mL THF. The reaction was stirred 1 h at room temperature and was quenched with saturated ammonium chloride solution (25 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL) and the organic layer was washed with brine (1×20 mL). The solution was dried with MgSO4, filtered and evaporated. Chromatography (silica gel, 30% ether/hexanes) gave 0.32 g of desired product; m.p.=109°-110° C.; 1H NMR (300 MHz, DMSO-d6) 9.43 (bs, 1H), 8.97 (bs, 1H), 7.62 (dd, J=1.50, 8.71 Hz, 2H), 7.25 (m, 2H), 6.96 (m, 1H), 6.15 (d, J=3.00 Hz, 1H), 5.38 (q, J=6.9, 17.4 Hz, 1H), 2.19 (s, 3H), 1.39 (d, J=6.30 Hz, 3H); MS (M+H)+ =261; Analysis calc'd for C14H16N2O3 : C, 64.59; H, 6.20; N, 10.77. Found: C, 64.00; H, 6.12; N, 10.60.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[NH2:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[F:18])=[O:6]
Reactant: Nc1ccc(F)cc1F
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2F)c(Cl)n1
Temperature: 23 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
2-Chloro-6-methylnicotinic acid (500 mg, 2.9 mmol) was suspended in CH2Cl2 (14.6 mL). Oxalyl chloride (0.3 mL, 3.5 mmol) was added followed by 3 drops of DMF and the reaction was stirred at 23° C. for 2 h. The solvent was removed by rotary evaporation and the residue was dried under vacuum. The crude acid chloride was dissolved in CH3CN (14 mL) and 2,4-difluorobenzenamine (0.33 mL, 3.2 mmol) was added followed by triethylamine (0.41 mL, 2.9 mmol). The reaction was stirred at 23° C. for 16 h and then concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and sat. aq. NaHCO3 soln (30 mL). A little water was added to help break up some of the residual salts. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organics were dried over MgSO4 and concentrated in vacuo. Trituration with hot 5% EtOAc-hexanes afforded the desired product as a light tan powder (559 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 2.60 (s, 3H), 6.82-7.09 (m, 2H), 7.22-7.32 (d, 1H, J=7.63 Hz), 8.18 (d, 1H, J=8.14 Hz), 8.28-8.50 (m, 1H), 8.57 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=[N:16][N:15]=2)=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O>ClC(Cl)(Cl)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:28][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A mixture of compound D (8.0 g; 21 mM), N-bromosuccinimide (4.53 g; 25 mM) and azo(bisisobutyronitrile) (73 mg) in 1,1,1-trichloroethane (methyl chloroform) (50 mL) was heated under reflux for 4 hours. The mixture was cooled to ambient temperature, washed with water (3×50 mL), and the suspended solid collected by filtration to give 5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (E) (7.3 g), m.p. 192°-195° C.; NMR (CDCl3): 4.4(2H, s), 6.52(2H, d), 6.85(2H, d), 7.07(2H, d), 7.4(1H, d) 7.7 (2H,m), 7.9(1H, d).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-methoxy-phenylboronic acid to give [1-(4-methoxy-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[OH:10])[CH3:3].C(=O)(O)[O-].[Na+]>CO.O.[Pt]=O>[CH2:2]([O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][CH2:8][CH:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)[OH:10])[CH3:3]
Reactant: CCOc1ccccc1OCC(O)c1ccccn1
Agent: O=[Pt]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Product: CCOc1ccccc1OCC(O)C1CCCCN1
Yield: 74.6 %

Procedure:
A solution of α-[(2-ethoxyphenoxy)methyl]-2-pyridinemethanol hydrochloride (10.0 g., 0.034 mole) in 150 ml of methanol was hydrogenated at room temperature for 2 hr in the presence of 1.40 g of platinum oxide. Solvent was removed by rotary evaporator and NMR showed that the desired piperidine compound was obtained (9.35 g). This hydrochloride salt was dissolved in 150 ml of water and the solution was made alkaline (pH=8) with sodium bicarbonate. The free base was extracted from this aqueous solution with methylene chloride. Removal of methylene chloride gave 6.73 g of α-[(2-ethoxyphenoxy)methyl]-2-piperidinemethanol. The entire amount of the piperidine-methanol derivative (6.73 g) was dissolved in a mixture of 50 ml of acetic anhydride and 50 ml of pyridine and the mixture was heated at 90° C. for 4 hr. The reaction mixture was then stirred overnight at room temperature. Excess acetic acid anhydride and pyridine were removed in vacuo. The sample was then pumped under vacuum to remove final traces of pyridine and acetic anhydride. Formation of the diacetate derivative was confirmed by mass spectral analysis. The diacetate (9.82 g, 0.03 mole, as a viscous oil) was dissolved in 100 ml of tetrahydrofuran. To this solution was added slowly and under nitrogen with stirring, lithium aluminum hydride (3.06 g, 0.078 mole). Vigorous evolution of hydrogen occurred. The reaction mixture was stirred for 2.5 hr at room temperature and then slowly quenched with isopropanol followed by water. The reaction mixture was filtered and washed with methanol. The solvent was removed in vacuo, and the resulting oil was then partitioned between water and chloroform. The chloroform was removed in vacuo to give 5.42 g of light brown oil. The maleate salt was prepared by mixing equimolar methanol solutions of the free base and maleic acid. Addition of diethyl ether caused crystallization of a solid. The solid was triturated with isopropyl ether followed by ethyl acetate to give 2.24 g (16.1%) of a brown solid, m.p. 111.5°-115.0° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)=[O:9].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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.CCOC(C)=O>[CH3:7][C:4]1[S:3][C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:8]=[O:9])=[N:6][N:5]=1
Reactant: Cc1nnc(Br)s1
Reactant: O=Cc1ccccc1B(O)O
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2ccccc2C=O)s1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (150 mg, 0.84 mmol) in 1,2-dimethoxyethane (5 mL) are added 2-formylphenylboronic acid (190 mg, 1.26 mmol), Pd(PPh3)4 (97 mg, 0.08 mmol) and Na2CO3 (sat., 0.10 mL) at room temperature. The solution is heated to 100° C. for 18 hours then cooled and poured into water and EtOAc. Layers are separated and the aqueous phase extracted with EtOAc (1×10 mL). The combined organics are dried (MgSO4), filtered and concentrated to give the crude product which is purified via flash chromatography (12 g silica gel, 5-60% EtOAc/hexanes). The product-containing fractions are combined and concentrated to give 2-(5-methyl-1,3,4-thiadiazol-2-yl)-benzaldehyde (100 mg, 58%) which is used without further purification.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[C:21]([Cl:37])=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH:25]=3)[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1.N1C=CC=CC=1.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48].CCOC(C)=O>C1COCC1.O>[Cl:37][C:21]1[CH:22]=[C:23]([F:36])[C:24]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[CH:25][C:20]=1[C:12]1[C:13](=[O:19])[N:14]([CH2:17][CH3:18])[C:15]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([NH:6][C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH:16]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(N)cc21
Reactant: COCC(=O)Cl
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)COC)cc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.9 %

Procedure:
A mixture of Example 21 (90 mg, 0.199 mmol) and pyridine (79 mg, 0.996 mmol) in THF (4 mL) was treated drop-wise with methoxy acetyl chloride (27 mg, 0.249 mmol) and stirred at RT for 22 h. Additional methoxy acetyl chloride (30 μL, 0.328 mmol) was added, the mixture heated at 40° C. for 6 h, then cooled to RT and stirred overnight. The mixture was treated with EtOAc and water, stirred for 1 h, the resulting solid collected via filtration and dried to afford N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-methoxyacetamide (76 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 9.09 (s, 1H), 8.73 (m, 2H), 8.27-8.20 (m, 2H), 8.00 (s, 1H), 7.58 (d, J=10.9 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.12 (s, 2H), 3.38 (s, 3H), 1.26 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 524.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(=Cc2ccc(Cl)c([N+](=O)[O-])c2)c2ccccc21
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A stirred solution of dimethyl 3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (4.84 g, 0.02 mol; prepared in a manner similar to that described in Example 23) and 4-chloro-3-nitrobenzaldehyde (3.71 g, 0.02 mol) in tetrahydrofuran (30 ml) was cooled to 15° C. and a solution of triethylamine (2.02 g, 0.02 mol) in tetrahydrofuran (3 ml) was added dropwise at <25° C. The mixture was stirred at ambient temperature for 1 hour, allowed to stand at this temperature for a further 16 hours and the resulting solid was collected by filtration. The filtrate was concentrated in vacuo, the residue was triturated with water (5 ml) and the resulting solid was collected by filtration. The two crops of solid were combined and suspended in water (30 ml). The mixture was stirred at ambient temperature for 30 minutes and the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-chloro-3-nitrobenzylidene)-3H-isobenzofuran-1-one as a pale yellow solid, m.pt. 198–204° C., still slightly wet with water, which was used directly in the next stage.
Reaction SMILES: I.[CH3:2][N:3](C)[C:4](=[NH:6])S.[NH2:8][CH2:9][C:10]([OH:12])=[O:11]>[OH-].[NH4+]>[CH3:2][N:3]=[C:4]([NH2:6])[NH:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CN(C)C(=N)S
Reactant: NCC(=O)O
Agent: I
Agent: [NH4+]
Agent: [OH-]
Product: CN=C(N)NCC(=O)O
Reaction time: 8 h

Procedure:
N,N-dimethylisothiourea hydroiodide (9.5 g., 0.041 mole) was added portionwise to a stirred solution of glycine (4.45 g., 0.0595 mole) in concentrated ammonium hydroxide (40 ml.) at room temperature. The reaction was stirred overnight and the product recovered by filtration as white crystals: 3.0 g., m.p. 230° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: OB(O)c1cccc(Br)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.45) (1.50 g, 5.42 mmol) and commercially available 3-bromo-benzeneboronic acid (1.31 g, 6.52 mmol) according to the general procedure IVb. Obtained as a white solid (1.17 g, 54%). MS (EI) 395.9, 397.9 [(M)+]; mp 111° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:9][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: BrCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccccc1COC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1.2 g of sodium hydride at 50% in suspension in oil are added at 5° C., in portions, to 5 g of cyclohexanol in solution in 150 ml of dimethylformamide. The mixture is stirred for 1 hour at room temperature and 12.5 g of 2-bromobenzyl bromide in solution in 15 ml of dimethylformamide are introduced at 5° C. After 2 hours at room temperature, the reaction medium is poured over ice-cold water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and evaporated to give 13.3 g of oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15](F)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCOCC1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccc(Nc2ncnc3cc(NCCCN4CCOCC4)ccc23)c1
Temperature: 110 °C
Yield: 77.7 %

Procedure:
To a solution of 4-[(3-bromophenyl)amino]-7-fluoroquinazoline (0.60 g, 1.89 mmol) in Dimethylsulfoxide (DMSO) (10 mL) was added 4-(3-aminopropyl)morpholine (7.54 mmol, 1.10 mL). The reaction mixture was heated at 110° C. for 26 hours and then diluted with water, basified by the addition of saturated NaHCO3 and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Column chromatography on Grade III alumina with gradient elution from EtOAc to EtOAc/MeOH (98:2) followed by recrystallization from EtOAc/hexane gave 4-[(3-bromophenyl)amino]-7-[(3-morpholinopropyl)amino]quinazoline (0.65 g, 78%) as cream crystals,