Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C.CCOC(C)=O>[N:31]([CH2:24][CH2:23][O:22][C@@H:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:30])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(Cl)cc1[C@H](OCCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1[C@H](OCCN=[N+]=[N-])[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 93.5 %

Procedure:
(R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (8.4 g, 18.3 mmol) was dissolved in anhydrous DMF (150 mL), solid NaN3 (3.56 g, 54.8 mmoL) was added and the reaction mixture was heated to 60° C. for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (500 mL), the organic phase was washed with water (5×50 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-((R)-(2-azidoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (7 g).
Reaction SMILES: [CH3:1][Mg]Br.COC(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.CC[O:17][CH2:18][CH3:19]>C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:18]([OH:17])([CH3:19])[CH3:1])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: COC(=O)c1cccc(Br)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93 %

Procedure:
To 75 mmol of methylmagnesium bromide in 25 mL of ether stirring at 6° C. is added, dropwise over 10 min, a solution of methyl-3-bromobenzoate (4.3 g, 20 mmol) in 25 mL of dry THF. The mixture is then allowed to warm to ambient temperature and stirred for 3.5 h, then cooled to 0° C. and quenched by dropwise addition of aqueous 10% HCl. The acidified mixture is extracted twice with ethyl acetate, and the combined organic phases are washed with 1 N NaHCO3 and with brine. The solution is dried over Na2SO4, concentrated, and chromatographed over silica gel, eluting with 15% ethyl acetate in heptane, to afford 4.00 g (18.6 mmol, 93%) of 2-(3-bromophenyl)-2-propanol 27 as a pale yellow oil: 1H NMR (CDCl3) δ 7.65 (t, J=2 Hz, 1H), 7.39 (m, 2H), 7.20 (t, J=8 Hz, 1H), 1.78 (br s, 1H), 1.57 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][CH2:19][C@:10]2([O:14][CH2:13][C:12]([Sn](C)(C)C)=[CH:11]2)[C@@H:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].Br[C:31]1[CH:32]=[C:33]([O:46][CH3:47])[CH:34]=[CH:35][C:36]=1[N:37]1[C:41]([C:42]([F:45])([F:44])[F:43])=[N:40][N:39]=[N:38]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][CH2:19][C@:10]2([O:14][CH2:13][C:12]([C:31]3[CH:32]=[C:33]([O:46][CH3:47])[CH:34]=[CH:35][C:36]=3[N:37]3[C:41]([C:42]([F:43])([F:44])[F:45])=[N:40][N:39]=[N:38]3)=[CH:11]2)[C@@H:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]2(C=C([Sn](C)(C)C)CO2)[C@@H]1c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nnnc2C(F)(F)F)c(C2=C[C@@]3(CCCN(C(=O)OC(C)(C)C)[C@H]3c3ccccc3)OC2)c1
Temperature: 110 °C
Yield: 89.7 %

Procedure:
A mixture of (5R,6S)-7-(tert-butoxycarbonyl)-6-phenyl-3-(trimethylstannyl)-7-aza-1-oxa-spiro[4.5]dec-3-ene (0.5 g, 1 mmol; Desc.6), lithium chloride (0.266 g, 6 mmol) and 3-bromo-4-(5-(trifluoromethyl)-tetrazol-1-yl)anisole (0.404 g, 1.2 mmol; Desc. 7c) in toluene (15 ml) was degassed and purged with nitrogen before addition of tetrakis(triphenylphosphine)palladium(0) (0.06 g). The mixture was degassed thoroughly, and the solution was heated to 110° C. for 19 hours. The solvent was evaporated in vacuo. The residue was dry loaded onto silica from methanol, and purified by chromatography on silica eluting with 10-20% ethyl acetate in hexane, to afford the title compound as a yellow oil (500 mg, 90%) MS (CI+) m/z 558 (M+H, 60%). 1H NMR (250 MHz, CDCl3) δ 1.34 (9H, s), 1.50 (1H, m), 1.55 (1H, m), 1.67 (1H, m), 1.87 (1H, m), 3.08 (1H, m), 3.88 (3H, s), 4.02 (1H, m), 4.30 (1H, dd, J 2.1 Hz, J 12.4 Hz), 4.46 (1H, dd, J 2.1 Hz, J 12.4 Hz), 4.92 (1H, s), 5.30 (1H, t, J 0.9 Hz), 6.68 (1H, d, J 2.8 Hz), 6.98 (1H, dd, J 2.8 Hz, J 8.8 Hz), 7.25 (6H, m).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:31][C:32](=O)[C:33]([F:36])([F:35])[F:34]>CC(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:31]=[C:32]([C:33]([F:36])([F:35])[F:34])[N:13]=[C:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(-c3cccs3)cc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cccs3)cc2)cc1
Temperature: 80 °C
Yield: 39.9 %

Procedure:
To a mixture of N-[4-(methylsulfonyl)phenyl]-4-(2-thienyl)benzenecarboximidamide (0.7 g, 1.96 mmol) and sodium bicarbonate (0.33 g, 3.93 mmol) in 2-propanol (30 mL) was added 3-bromo-1,1,1-trifluoroacetone (0.449 g, 2.35 mmol). After the reaction mixture was heated to 80° C. for 21 hours, the solvent was removed. The residue was redissolved in CH2Cl2 (50 mL) and washed with water (30 mL×2). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1) to give the subtitle compound (0.351 g, 30.1% yield, via 2 steps).
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(OC)=[O:2].C(N(CCC)CCC)CC>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[CH2:11][CH:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:1](=[O:2])[N:21]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:20][C:13]=2[CH:14]=1
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CNCC(F)(F)F)C(=O)OC
Agent: CCCN(CCC)CCC
Product: COC(=O)CC1Cc2ccc(OC)cc2CN(CC(F)(F)F)C1=O
Yield: 92.4 %

Procedure:
A mixture of methyl (±)-3-carbomethoxy-4-[2-(2,2,2-trifluoroethylamino)methyl-4-methoxyphenyl]butanoate (16.71 mmole), tripropylamine (9.5 mL, 50.13 mmole), and xylenes (170 mL) was heated at reflux. After 63 hr the reaction was concentrated, and the residue was chromatographed on silica (2:1 EtOAc/hexanes, load with CH2Cl2). The title compound (5.33 g, 92% for two steps) was obtained as a light yellow solid: TLC (40% EtOAc/hexanes) Rf 0.49; 1H NMR (250, CDCl3) δ 7.04 (d, J=8.5 Hz, 1 H), 6.80 (dd, J=8.5, 2.6 Hz, 1 H), 6.61 (d, J=2.6 Hz, 1 H), 5.35 (d, J=16.8 Hz, 1 H), 3.60-4.30 (m, 4 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 2.81-3.15 (m, 3 H), 2.46 (dd, J=16.9, 5.5 Hz, 1 H); MS (ES) m/e 368 (M+Na)+, 346 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCN)cc(OC)c1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCNC(=O)CCc2ccc(F)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(3,5-Dimethoxy-phenyl)ethylamine (1.20 g, 6.62 mmol) is dissolved in anhydrous DMF (50 mL), and 3-(4-fluorophenyl) propionic acid (1.113 g, 6.62 mmol), PyBOP (3.77 g) and DIPEA (2.61 mL, 15 mmol) are added. The mixture is stirred at rt for 14 h. Water (60 mL) is added, and the mixture is extracted with EtOAc (4×60 mL). The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography (EtOAc/Hex, 7:3) to afford the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:13][CH:14]([OH:17])[CH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OC(O)C)C>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]([F:9])([F:10])[F:11]
Reactant: OCC(O)CCl
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cccc(C(F)(F)F)c1CC(O)CO

Procedure:
In a two liter three necked flask equipped with mechanical stirrer, refluxing condenser and thermometer was added 322.2 gms (2.0 moles) of 3-aminobenzotrifluoride, 500 ml of ethoxyethanol solvent and 442.0 gms (4 moles) 1-chloro-2,3-propanediol. While this mixture was cooling, 205 gms (2.36 moles) of sodium carbonate was added keeping the temperature below 35° C. The mixture was then heated to reflux for 24 hours. Afterwards, the crude reaction mixture was filtered from the salt by-product. The salt was then washed several times with chloroform and these washings were combined with the filtrate. The solvent and chloroform was then removed under low vacuum and high vacuum to give 450.5 gms of the crude bis-2,3-dihydroxypropyl-3-aminobenzotrifluoride as a viscous dark oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 73.2 %

Procedure:
A mixture of 1.00 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 1.44 g of methyl 11-bromoundecanoate and 1.00 g of anhydrous potassium carbonate in 20 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 2 hours. The usual workup followed by chromatography on 30 g of silica gel and elution with 10% ethyl acetate-toluene gave 1.48 g (76% yield) of 11-(4-Acetyl-3-hydroxy-2-propylphenoxy) undecanoic acid methyl ester, the titled compound, as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:11].[Cl-].[CH2:13]=[N+:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:20][C:3]1[C:2]([CH3:1])=[C:10]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]2[C:4]=1[C:5]([NH2:11])=[N:6][CH:7]=[N:8]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cc2c(N)ncnn2c1
Reactant: C=[N+]1CCOCC1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Temperature: -78 °C
Reaction time: 17 h
Yield: 77.9 %

Procedure:
To a solution of 6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (350 mg, 2.36 mmol) in DMF (5 mL), was added 4-methylenemorpholin-4-ium chloride (Eur. J. Med. Chem. 1989, 24, 379-384) (750 mg, 2.84 mmol) at rt. The reaction was stirred for 17 hr, cooled to −78° C., and treated with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (337 mg, 1.18 mmol). The reaction was allowed to stir for 30 minutes while warming to rt. The mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous Na2CO3 solution (150 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. Trituration with acetonitrile afforded 300 mg (39%) of the desired product. 1H-NMR (DMSO-d6) δ 7.83 (s, 1H), 3.76 (s, 2H), 3.50-3.47 (m, 4H), 2.36-2.32 (m, 4H), 2.15 (s, 3H); MS [M+H]+=325.9, 327.9; LCMS RT=1.10.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1)=[O:18])=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4].[NH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1>CN1C(=O)CCC1>[Cl:27][C:9]1[CH:8]=[C:7]2[C:12]([C:13](=[O:26])[C:14]([CH2:15][NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:35]4[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]4)=[N:21][CH:20]=3)=[O:18])=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:34])[N:6]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][CH:10]=1
Reactant: CN(C)C(=O)c1c(CNC(=O)c2ccc(Cl)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: OCC1CCNCC1
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCC(CO)CC3)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 125 °C

Procedure:
The intermediate 7-chloro-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (70 mg, 0.141 mmol) was combined with piperidin-4-ylmethanol (40 mg, 0.346 mmol) and NMP (2 mL). The reaction mixture was heated at 125° C. for 2 hr. After this time, the crude product was subjected to preparative reverse-phase HPLC purification. The product, 4-hydroxymethyl-3,4,5,6-tetrahydro-2H[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-2-dimethylcarbamoyl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was obtained as 30 mg (37%) of a white solid. MS calcd. for C31H32ClN5O4 [(M+H)+] 574.2, obsd. 574.3.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:27]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:24]=[CH:25][CH:26]=3)[CH:22]=[O:23])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 120 °C
Yield: 77.6 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (390 mg) and tripotassium phosphate (954 mg) in N,N-dimethylformamide (DMF) (3 mL) and water (0.75 mL) stirred under nitrogen was added Pd(Ph3P)4 (173 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was diluted with ethyl acetate (50 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated, the residue was purified by column chromatography to give 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylbenzaldehyde (D53) (450 mg) as an oil. MS (ES): C20H19ClN2O2S requires 386. found 387.1 (M+H+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[ClH:31].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:37]([CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)[CH3:36])=[CH:9][CH:10]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1
Reactant: CNC1CCCCC1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)cc2)C3)cc1
Product: CN(CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)cc2)C3)cc1)C1CCCCC1
Product: Cl

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methylcyclohexanamine was used instead of piperidine to afford 6-(4-chlorophenyl)-N-(4-(2-(cyclohexyl(methyl)amino)ethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine hydrochloride. M.p.=157-163° C. 1H NMR 400 MHz (DMSO) δ 9.94 (bs, 1H), 9.61 (s, 1H), 8.34-8.29 (m, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.54-7.45 (m, 2H), 7.35-7.31 (m, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.16-7.09 (m, 3H), 4.44 (t, J=6.4 Hz, 1H), 3.40-3.07 (m, 4H), 3.02-2.95 (m, 2H), 2.75 (d, J=4.8 Hz, 3H), 2.08-1.98 (m, 2H), 1.84-1.78 (m, 2H), 1.63-1.06 (m, 7H). LCMS m/e 523 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.Br.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: C=CC(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Under ice cooling, 3.0 g of acryloyl chloride dissolved in 50 ml of tetrahydrofuran was added dropwise to a suspension of 5.03 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide in 150 ml of ethyl acetate and 150 ml of water containing 4.52 g of potassium carbonate, and the mixture was stirred for 3 hours. Crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol-acetonitrile to obtain 3.69 g of 2-acryloylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:33]=[CH:32][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([NH:28]C(=O)C)[CH:19]=[C:20]([C:22]5[O:23][C:24]([CH3:27])=[CH:25][CH:26]=5)[CH:21]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1>C(O)C.O.C(OCC)(=O)C>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:33]=[CH:32][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([CH:19]=[C:20]([C:22]5[O:23][C:24]([CH3:27])=[CH:25][CH:26]=5)[CH:21]=4)[NH2:28])[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1
Reactant: CC(=O)Nc1cc(-c2ccc(C)o2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(N)cc(-n3cnc4cc(-c5cnn(C)c5)ccc43)c2)o1
Yield: 92 %

Procedure:
A mixture of KOH (0.614 g, 10.94 mmol) and the compound of Example 73 (3.0 g, 7.29 mmol) in ethanol (5 ml) and water (2 ml) was heated at 60° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and was washed with water (50 ml) and brine (25 ml). The organic phase was dried over sodium sulfate and concentrated under vacuum and the residue was purified by column chromatography to afford the product in 92% yield (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=1[C:25]#[N:26].Br[CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:24]=1[C:25]#[N:26]
Reactant: CC(C)(CO)CBr
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCC(C)(C)CO
Temperature: 65 °C
Reaction time: 24 h

Procedure:
4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (200 mg, 0.46 mmol) was dissolved in DMF (2 mL) and 3-bromo-2,2-dimethyl-propan-1-ol (72 μL, 0.94 mmol) and K2CO3 (192 μL, 1.08 mmol) were added. The mixture was stirred at 65° C. for 24 hrs, cooled to rt, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. Silica gel column chromatography (1% MeOH in DCM with gradient up to 5% MeOH in DCM) followed by prep HPLC afforded 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-[2-(3-hydroxy-2,2-dimethyl-propoxy)-phenyl]-N-methyl-benzamide. MS: 518.3 (M+H)+, tR=6.16 min (method 3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H](C2C=CC(F)=CC=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[C:26](OCC)(=O)CC(C)=O.[Br:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH:38]=O.ClC1C=C(F)C=CC=1C=O>>[Br:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[C@H:38]1[C:5]([C:3]([O:2][CH2:1][CH3:26])=[O:4])=[C:10]([CH2:11][Br:12])[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Br
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: O=Cc1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br

Procedure:
Ethyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 70a was prepared in analogy to compound C with procedures shown in Example 1 by using ethyl acetoacetate and 2-bromo-4-fluoro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde, respectively.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[Cl-:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCCCl
Reactant: Cn1ccnc1
Product: CCCCn1cc[n+](C)c1
Product: [Cl-]
Reaction time: 4 h

Procedure:
The procedure of Example 1 was repeated with minor changes. 549 g of 1-chlorobutane and 487 g of 1-methylimidazole were added into a 2000 ml three-neck round-bottom flask. The reaction temperature was set from 75 to 80° C. After four hours, the milk-like solution transferred into homogenous solution. The reaction was continued for three days. Then, the product was washed with ethyl acetate five times. After that, it was dried in vacuum for three days.
Reaction SMILES: [Br-:1].C([N:4]([CH2:7][CH3:8])CC)C.[CH3:9][C:10]([S:13](Cl)=[O:14])([CH3:12])[CH3:11]>C(Cl)Cl>[Br:1][CH2:8][CH2:7][NH:4][S:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)S(=O)Cl
Reactant: [Br-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 2-bromoethaneamomium bromide (410 mg, 2 mmol) in 20 mL of CH2Cl2 was added triethylamine (3697 μL, 5 mmol). The resulting mixture was stirred at a temperature of about 25° C. for 30 min, then cooled down at 0° C. 2-methylpropane-2-sulfinic chloride (0.73 mL, 2.2 mmol) was added dropwise, kept stirring for 1 hr and allowed to warm up to a temperature of about 25° C. and stirred for about 16 hours. The resulting mixture was condensed and purified by flash chromatography to provide 2-methyl-propane-2-sulfinic acid (2-bromo-ethyl)-amide as a white solid (0.42 g, 86% yield).