Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH:13]([OH:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[OH:16][CH:13]1[C:12]2[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=2[C:6]2[CH:7]=[C:2]([C:22]#[C:21][C@:23]3([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:3]=[CH:4][C:5]=2[O:15][CH2:14]1
Reactant: COC(=O)c1nc2c(s1)C(O)COc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: COC(=O)c1nc2c(s1)C(O)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (0.37 g) was subjected to General Procedure 0 to afford 280 mg (75%) of methyl 9-bromo-4-hydroxy-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Methyl 9-bromo-4-hydroxy-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (128 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford methyl 4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 25 mg and 7.9 mg (26% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(OCC)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(C)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C(=O)Cl)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 60 ml of anhydrous ethyl ether, was suspended 6.2 g of 4-acetyloxy-2-methylbenzoic acid. To the suspension, was added 8.0 g of phosphorus pentachloride. The suspension was stirred for 3 hours at room temperature. The reaction mixture was freed from the solvent by distillation under reduced pressure, admixed again with ethyl ether, and freed from the solvent by distillation to obtain 4-acetyloxy-2-methylbenzoyl chloride.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[F:22]C1C=CC(F)=CC=1C(O)=O>>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Product: CCOP(=O)(C=C1NCCN(C)c2ccc(F)cc21)OCC

Procedure:
(7-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, prepared in Example 1, by replacing 2-fluorobenzoic acid with 2,5-difluorobenzoic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])=[N:3]1.[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:32])[C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])[C:19]([CH3:21])=O>>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17]([C:18]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:5]2[C:4]([CH2:8][CH:9]([CH3:11])[CH3:10])=[N:3][N:2]([CH3:1])[C:6]=2[NH:7][C:19]=1[CH3:21])=[O:32]
Reactant: CC(C)Cc1cc(N)n(C)n1
Reactant: COCCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Product: COCCOC(=O)C1=C(C)Nc2c(c(CC(C)C)nn2C)C1c1ccccc1[N+](=O)[O-]

Procedure:
Starting from 1-methyl-3-(2-methylpropyl)-5-pyrazolamine and 2-methoxyethyl-2-(2-nitrobenzyliden)acetoacetate.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=O)=[CH:5][CH:4]=[C:3]([Br:11])[CH:2]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[S:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]1[S:19][CH:9]=[C:7]([C:6]2[CH:5]=[CH:4][C:3]([Br:11])=[CH:2][CH:1]=2)[N:18]=1)[CH3:13]
Reactant: CCOC(=O)CC(N)=S
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(Br)cc2)cs1

Procedure:
A mixture of p-α-dibromoacetophenone (13.9 g, 0.05 mole) and 2-thiocarbamoylacetic acid ethyl ester in ethanol (65 ml) was heated under reflux for 21/2 hours. On cooling, there was obtained the title compound (12.2 g) mp 189°-191° C. (dec). An analytical sample recrystallized from ethanol had mp 191°-193° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:40])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][CH2:25][C@H:26]([OH:39])[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:4].Cl>CO.[OH-].[Na+]>[OH:39][C@H:26]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=1)[CH2:25][NH:24][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[O:40])=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1ccc(N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(c3ccc(C(=O)N4CCC[C@H]4C(=O)O)cc3)CC2)ccc1O
Yield: 121.9 %

Procedure:
A solution (2S)-1-[4-(4-{[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]-phenyl}-ethyl)amino]methyl}piperidin-1-yl)benzoyl]-pyrrolidine-2-carboxylic acid methyl ester (0.072 g, 0.12 mmol) in methanol (2 mL) and 1N sodium hydroxide (0.37 mL) was stirred at ambient temperature overnight. The reaction mixture was neutralized with 1N HCl (0.37 mL) and concentrated in vacuo. The residual solid was washed with water, then ether to give reasonably pure product (0.082 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(F)cc1

Procedure:
A 12-Liter 3-neck round-bottom flask equipped with a nitrogen inlet, an overhead mechanical stirrer, was charged with 6 Liters of methanol, the 1-fluoro-4-(trimethylsilyl)ethynylbenzene (1432 g) prepared above, and 98 g of anhydrous potassium carbonate. Stirring was continued until no starting material was detected by gas chromatographic analysis (about 1 hour).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:21]#[C:20][C:22]2([OH:30])[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1ccc(Br)c(Cc2ccccc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 720 mg of 2-benzyl-3-bromo-6-(2-methoxyethyloxy)pyridine, 340 mg of 3-ethynyl-3-quinuclidinol, 130 mg of tetrakis(triphenylphosphine)palladium(0), 42 mg of cuprous iodide, 0.93 ml of triethylamine and 3 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 80° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to give 500 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C:33]1C(=O)NC=CC=1.C(N(C(C)C)C(C)C)C.C(O)C(N)(CO)CO>ClCCl>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C:17]1[C:18](=[O:22])[NH:19][CH:20]=[CH:33][CH:21]=1)=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2
Reactant: Nc1ccc[nH]c1=O
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)Nc3ccc[nH]c3=O)cc21
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (Example 16; 100 mg, 0.226 mmol) in dichloromethane (1.1 mL) was added 3-aminopyridin-2(1H)-one (26.1 mg, 0.237 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.039 mL, 0.226 mmol). After 48 h, the reaction was treated with tris-amine resin (silica supported amine 3, 100 mg, loading=1.76 mmol/g). After 45 minutes, the reaction was filtered though a silica gel plug, washing well with ethyl acetate. The filtrate was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organics were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with a gradient of 50% to 100% ethyl acetate/hexanes to yield 5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamide (32 mg, 32%). Mass spec: 439 (M+1). 1H NMR (CDCl3) δ 10.8 (s, 1H), 8.68 (dd, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.28-6.88 (m, 6H), 6.36 (dd, 1H), 4.25 (d, 2H), 2.38 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[N+:10]([CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)([O-])=[O:11].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][C:13]1[CH2:3][CH:2]([CH2:1][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[O:11][N:10]=1
Reactant: C=CCN1CCOCC1
Reactant: O=[N+]([O-])CCOC1CCCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: C1CCC(OCC2=NOC(CN3CCOCC3)C2)OC1
Temperature: 55 °C
Yield: 44.3 %

Procedure:
To a solution of N-allylmorpholine (0.76 g, 5.0 mmol) in toluene (10 mL) was added 2-(2-nitroethoxy)tetrahydropyran (1.34 g, 7.7 mmol), phenylisocyanate (2:43 g, 20.1 mmol), and triethylamine (52 mg; 0.5 mmol). The resulting mixture was heated at 55° C. overnight. After cooling to room temperature the formed precipitate was removed by filtration and the remaining solution concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 96/3.75/0.25) to yield 0.63 g (44%) of [5-((morpholin-4-yl)methyl)-4,5-dihydro-isoxazol-3-yl]methyl 2-tetrahydropyranyl ether. MH+ 285, Rf 0.34 (CH2Cl2/MeOH/NH4OH 96/3.75/0.25).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20](O)=[O:21])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20](=[O:21])[N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: C1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCCCC1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 66 %

Procedure:
The title compound (37 mg, 66%) was prepared from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and piperidine as in Example 1, Part C. HPLC: RT=11.00 min. MS (ESI−): mass calcd. for C27H24Cl3N5O4S2, 653.00; m/z found, 650/652 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.70 (m, 1H), 8.38 (d, J=7.0, 1H), 8.21 (d, J=8.8, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.69 (d, J=1.9, 1H), 7.35 (d, J=8.2, 1H), 7.28-7.25 (m, 1H), 7.22 (d, J=1.9, 1H), 7.13 (d, J=7.4, 1H), 6.99 (dd, J=8.2, 1.9, 1H), 6.92 (dd, J=8.4, 1.9, 1H), 5.26-5.21 (m, 1H), 3.62-3.49 (m, 2H), 3.43-3.35 (m, 1H), 3.26-3.19 (m, 1H), 3.08-2.95 (m, 2H), 1.70-1.46 (m, 5H), 1.33-1.23 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25]>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH:24]([CH3:26])[CH3:25])[CH:32]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(C(C)C)c4)c(C(=O)O)s3)c2cc1OC
Yield: 43.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-isopropylphenylboronic acid (24.6 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-isopropyl-phenyl)-thiazole-5-carboxylic acid (18.6 mg, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.61 (br.s., 1 H); 8.83 (s, 1 H); 7.88 (s, 1 H); 7.83 (t, 1 H); 7.74 (dt, 1 H); 7.39 (s, 1 H); 7.40 (t, 1 H); 7.36 (dt, 1 H); 3.86 (s, 3 H); 3.85 (s, 3 H); 2.93-3.03 (m, 1 H); 1.26 (d, 6 H). MS m/z 424 (M+1 ).
Reaction SMILES: Br.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3Br)=[CH:8][CH:9]=[CH:10][C:3]1=2.C([Mg]Cl)C.[CH3:24][S:25]SC>O1CCCC1>[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[S:25][CH3:24])=[CH:8][CH:9]=[CH:10][C:3]1=2
Reactant: BrC1=C(c2cccc3sccc23)N2CCN=C2S1
Reactant: CSSC
Agent: Br
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CSC1=C(c2cccc3sccc23)N2CCN=C2S1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
3-(Benzo[b]thiophen-4-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (15 g; prepared in a manner similar to that described in Example 22) was added in portions under nitrogen at 0-5° C. over 20 minutes to a stirred solution of ethylmagnesium chloride (2M solution in ether; 45 ml) in tetrahydrofuran (225 ml), then the mixture was stirred at 0-5° C. for 2 hours. The mixture was cooled to 0° C. and dimethyl disulphide (5.4 ml) was added, then the mixture was stirred at ambient temperature for 18 hours and quenched by the addition of saturated aqueous ammonium chloride solution (150 ml). The majority of the tetrahydrofuran was removed in vacuo, the residue was diluted with water (200 ml) and the product was extracted into ethyl acetate (400 ml). The extract was washed with water (300 ml) and saturated aqueous sodium chloride solution (2×150 ml), then it was dried (Na2SO4), and the solvents were removed in vacuo. The residue was purified by Biotage flash chromatography over silica using a 96:4 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 3-(benzo[b]thiophen-4-yl)-2-(methylthio)-5,6-dihydroimidazo[2,1-b]thiazole (7.3 g) as a pale yellow solid, m.p. 104-107° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:6]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)=[O:11])([CH3:8])[CH3:7])#[N:5].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[OH:3][NH:2][C:4]([C:6]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1)=[O:11])([CH3:8])[CH3:7])=[NH:5]
Reactant: CC(C)(C#N)NC(=O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)nc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)nc1)C(=N)NO
Temperature: 25 °C
Yield: 10.3 %

Procedure:
0.16 g hydroxylamine hydrochloride was added to a room temperature solution of 0.28 g 1-(6-trifluoromethyl-pyridin-3-yl-methoxy)-naphthalene-2-carboxylic acid (cyano-dimethyl-methyl)-amide and 0.50 g potassium carbonate in 5 ml 95% ethanol, and the resulting mixture was heated at reflux for 24 h. The reaction mixture was cooled to room temperature, diluted with 100 ml ethyl acetate, and was washed twice with 100 ml sat. sodium hydrogen carbonate solution and 100 ml brine. The combined organic layers were dried over sodium sulphate, and concentrated in vacuo to give an orange oil. Purification of the residue by RP-HPLC afforded 0.031 g of 1-(6-trifluoromethyl-pyridin-3-yl-methoxy)-naphthalene-2-carboxylic acid [1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-amide as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>CCCCCC.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Yield: 11.9 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 30 from 0.293 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, (-) isomer, and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography twice on silica using a DCM/AcOEt mixture (90/10; v/v) as the eluent gives 0.065 g of the expected product after crystallization and then recrystallization from a DCM/iso ether mixture and drying at 90° C. under vacuum. αD25 =-133° (c=0.24; chloroform).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=1.[BrH:13]>CC(O)=O>[BrH:13].[NH2:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][NH:5][C:4](=[O:3])[CH:9]=1
Reactant: COc1cc(CCN)ccn1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: NCCc1cc[nH]c(=O)c1
Yield: 86 %

Procedure:
A solution of 2-(2-methoxypyridin-4-yl)ethanamine hydrochloride (0.8 g, 4.23 mmol) was dissolved in 45% HBr (7 mL) and HOAc (7 mL). The mixture was heated to reflux for 4 hours and then the solvent was removed under reduce pressure. The residue was washed with THF (20 mL) and dried to give 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (0.8 g 86%) as a grey solid. LC-MS: 139 [M+H]+, tR=0.28 min.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[C:24](OC)([N:26]([CH3:28])[CH3:27])[CH3:25]>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:24]([CH3:25])=[CH:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(C)(OC)N(C)C
Reactant: CCOC(=O)c1cn(CC)c2cc(C(C)=O)ccc2c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(C(=O)C=C(C)N(C)C)ccc2c1=O

Procedure:
A mixture of 32.6 g ethyl 7-acetyl-1,4-dihydro1-ethyl-4-oxo-3-quinolinecarboxylate, 24 ml dimethylacetamide dimethylacetal and 100 ml DMF was heated on a steam bath for 4 hrs. The reaction mixture was concentrated in vacuo and the solid residue triturated with ethyl acetate. The solid product was recrystallized from acetonitrile to give 20.9 g ethyl 7-[3-(dimethylamino)-1-oxo2-butenyl]-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate, yellowish-orange powder, m.p. 178-179.5° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:24])=[C:21]([F:23])[F:22]>>[C:1]1([C:7]2[N:8]=[C:9]([S:18][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])[NH:10][C:11]=2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)=C(F)F
Reactant: Sc1nc(-c2ccccc2)c(-c2cccnc2)[nH]1
Product: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2cccnc2)[nH]1

Procedure:
4-Phenyl-5-(3-pyridyl)-1H-2-imidazolethiol (2.0 g; 7.9 mmoles) was reacted with 5.0 g (50 mmoles) of tetrafluoroethylene and the crude product purified by chromatography on Silicar CCNo. 7 with chloroform to afford 800 mg of 4-phenyl 5-(3-pyridyl)-2-(1,1,2,2-tetrafluoroethylthio)-1H-imidazole, m.p. 153°-154° (recrystallized from toluene).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[H-].[K+]>C1COCC1>[I:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:18]#[N:19])=[C:7]2[O:4][CH2:3][CH:2]([CH3:5])[CH3:1]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CC(C)CO
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)COc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 2-methyl-propan-1-ol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 6-iodo-4-isobutoxy-quinoline-3-carbonitrile. LC-MS m/e 353(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.[CH3:19][C:20]([S:23]([NH2:26])(=O)=[O:24])([CH3:22])[CH3:21]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[N:26][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: CC(C)(C)S(N)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (2.010 g, 6.63 mmol) and 2-methyl-2-propane sulfonamide (804 mg, 6.63 mmol) in anhydrous THF (22 mL) is added Ti(OEt)4 (3.025 g, 2.80 mL, 13.22 mmol). The resulting mixture is heated to reflux for 20 h. Brine (10 mL) is added after the mixture is cooled to rt, and stirred vigorously for 10 min. The mixture is filtered through a pad of Celite, and washed with ethyl acetate (50 mL). The filtrate is washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified through chromatography on silica gel to afford N-(6-bromo-2-phenylchroman-4-ylidene)-2-methylpropane-2-sulfinamide 1.05 g, 39%) as a light yellow solid. MS ESI+ve m/z 406 (M+H)+.