Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=C(N)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[OH-].[Na+].N.Cl>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([SH:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2c(N)cccc2s1
Agent: Cl
Agent: N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(S)c1N
Temperature: 260 °C

Procedure:
The thus obtained bisaminobenzothiazole compound [II] is added to an aqueous solution of an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide in an inert gas atomosphere at a temperature of about 110° to about 130° C., and then the mixture is slowly heated to about 260° C. to conduct reaction until generation of ammonia is ceased. Then, the temperature is lowered down to about 200° C. After addition of water thereto, the reaction mixture is cooled down to room temperature. Then, an aqueous dilute solution of an inorganic acid such as a concentrated hydrochloric acid is added to the reaction mixture to make pH 6, and then glacial acetic acid is added thereto to obtain a bisaminothiophenol compound [I] as precipitates.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:32]#[N:33])=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1B(O)O>>[C:32]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:37]2[CH:38]=[CH:39][C:40]([C:42]([F:45])([F:44])[F:43])=[CH:41][C:36]=2[O:35][CH3:34])=[N:3][CH:4]=1)#[N:33]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(C#N)c3c2)c(OC)c1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(C#N)c2cc(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
Example 240 was synthesized in a similar manner to Example 228, except that 1-chloro-4-cyano-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 0 to 10% MeOH:EtOAc) to afford 4-cyano-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.07 (s, 1H), 9.29 (s, 1H), 8.52 (d, J=1.3 Hz, 1H), 8.06 (dd, J=1.8, 8.8 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 7.65-7.60 (m, 1H), 7.56 (s, 1H), 7.55-7.52 (m, 1H), 7.32 (d, J=4.5 Hz, 1H), 6.93 (d, J=4.5 Hz, 1H), 3.76 (s, 3H). m/z (ESI) 491.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[BH4-].[Na+]>C(O)C.O>[OH:11][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(O)c1cccs1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a stirred solution of methyl 2-thiopheneglyoxylate (1.01 g) in ethanol (20 ml) in an ice bath was added sodium borohydride (0.113 g) in 1 ml of water, and the mixture was stirred for 10 minutes. The reaction was quenched with aqueous acetic acid and the mixture was partitioned between methylene chloride and water. The organic extract was washed with brine, dried (sodium sulfate) and evaporated to give methyl α-hydroxy-2-thienylacetate as an oil (0.903 g).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[CH:21]=[N:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([NH:28][C:2]3[CH:17]=[C:6]4[C:7]5[C:12]([CH2:13][CH2:14][N:5]4[C:4](=[O:18])[N:3]=3)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=5)=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccc3[nH]ncc3c2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 1H-indazol-5-ylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 13.00 (br, 1H), 9.60 (s, 1H), 8.36 (br, 1H), 8.06 (s, 1H), 7.69 (d, 1H), 7.51 (m, 2H), 7.10-6.95 (2H), 6.35 (s, 1H), 3.99 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 360.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@H:9]2[S:8][C:7]=1[NH2:27])(=O)C.[C:28]1([O:35][CH3:36])[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:30]>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:30][C:29]1[CH:31]=[CH:32][C:33]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:26])[C@@H:16]([C:17](=[O:25])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@H:9]3[S:8][C:7]=2[NH2:27])=[CH:34][C:28]=1[O:35][CH3:36]
Reactant: CC(=O)OCC1=C(N)S[C@@H]2[C@H](C(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: COc1ccccc1O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC2=C(N)S[C@@H]3[C@H](C(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)ccc1O
Reaction time: 0.25 h

Procedure:
11.7 Grams of 3-acetyloxymethyl-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid are dissolved in a solution of 18.6 g of guaiacol in 300 ml of trifluoroacetic acid and the mixture is left to stand to 15 minutes at room temperature, then diluted with an equal volume of toluene and evaporated under reduced pressure. The residue is partitioned between ethyl acetate and an aqueous dipotassium hydrogen phosphate buffer solution (pH 7.5) and the layers are separated. The aqueous layer is thoroughly washed with ethyl acetate, its pH then adjusted to 2.5 with 20% aqueous phosphoric acid and again extracted with ethyl acetate. The latter extracts are washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is recrystallised from ethyl acetate to yield the 3-(4-hydroxy-3-methoxy-benzyl)-7β-phenylacetyl-amino-ceph-2-em-4ξ-carboxylic acid, m.p. 198-199°; thin-layer chromatogram (silica gel): Rf = 0.76 (system n-butanol/acetic acid/water 67:10:23) and Rf = 0.43 (system n-butanol/ethanol/water 40:10:50); ultraviolet absorption spectrum (in methanol): λmax = 235 mμ (ε = 6800) and 282 mμ (ε = 1820); infrared absorption spectrum (in mineral oil): characteristic bands at 2,85μ, 2,99μ, 5,67μ, 5.74μ and 6.56μ. It is possible to obtain a further amount of the desired product from the mother liquor via the diphenylmethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH:22][CH3:23].[Cl-].[Na+]>O1CCCC1>[OH:17][CH2:18][CH2:19][CH:15]([C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]([N:22]([CH3:23])[CH3:21])=[O:20]
Reactant: CNC
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of the oil containing the two diasteriomers of dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-2(3H)-furanone (described in Example 1, 15 g, 0.055 mole) in tetrahydrofuran (200 ml) and an aqueous solution of dimethylamine (40%, 200 ml) is refluxed for 24 hr. Aqueous sodium chloride solution is added and the solution is extracted with diethyl ether. The organic extract is dried and evaporated to afford an oil consisting of two diasteriomeric amides of the title compound. The oil is subjected to chromatography on silica gel using acetone-benzene (1:3). The eluates are evaporated and crystallized from benzenehexane to obtain isomer A of the title compound as crystals (4.5 g), mp 158°-160° C. Further elution of the column with acetone-benzene (1:1), evaporation of the eluates and crystallization of the residue from benzene-hexane gives isomer B of the title compound as crystals (1.5 g), mp 159°-162° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])[OH:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH2:28][CH3:29]>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16]2)[C:6]=1[F:17])[OH:4]
Reactant: OC(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(C(O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodopropane (0.01 g). MS m/z (rel. intensity, 70 eV) 319 (M+, 4), 291 (14), 290 (bp), 220 (3), 149 (3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:33]O)[CH2:32][CH2:31]1.[K+].[Br-]>>[CH:30]1([CH2:33][O:24][C:23]([C:18]2([C:20]([OH:22])=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCC1CC1
Agent: [Br-]
Agent: [K+]
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OCC1CC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclopropylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO) δ 0.25 (q,2H), 0.49 (q,2H), 1.01 (d,3H), 1.10 (m,1H), 2.49 (m, 1H), 2.85-3.20 (m,4H), 3.94 (d, 2H) 4.85 (bt, 1H), 6.58 (d, 1H), 6.76 (m,2H), 7.35(m,3H), 7.46(s,1H); IR (KBr): 1653 cm-1 (C=O), 1747 cm-1 (C=O); MS (CI) m/z 476 (MH+). Anal. Calcd. for C24H26ClNO7 : C, 60.57; H, 5.51; N, 2.94; Cl, 7.46. Found: C, 56.38; H, 5.16; N, 2.61; Cl, 7.60.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:6]1[CH2:10][CH2:11][O:12][CH:5]1[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cccc(C2OCCO2)c1
Yield: 64.4 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (91.6 g, 0.75 mol) in 500 ml toluene is added ethylene glycol (333.0 g, 5.3 mol) and p-toluenesulfonic acid (0.19 g, 0.001 mol). The flask is equipped with a Dean-Stark trap and the mixture is refluxed for 2 days, extracted with saturated sodium bicarbonate solution and the organic phase separated and dried (MgSO4). Filtration and evaporation of solvent gives the title product as an oil (80.3 g, 64% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: Fc1ccc(/C=C/CBr)cc1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Product: Cc1cc(OC/C=C/c2ccc(F)cc2)c(C)c(C)c1NC=O
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-fluorobenzene, the title compound was synthesized according to Reference Example 17a.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCBr
Reactant: C1CCN(C2CCNCC2)CC1
Product: N#CCN1CCC(N2CCCCC2)CC1

Procedure:
The title compound is synthesized by coupling of [1,4′]Bipiperidinyl (commercially available from Fluorochem Ltd) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=208.2.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])[CH3:8].[C:24]([O:32][C@@H:33]1[CH2:41][C@@H:36]2[O:37][C:38](=[O:40])[CH2:39][C@@H:35]2[C@H:34]1/[CH:42]=[CH:43]/[C@H:44]([C:46]1[S:50][C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[CH:47]=1)[OH:45])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[C:24]([O:32][C@@H:33]1[CH2:41][C@@H:36]2[O:37][C:38](=[O:40])[CH2:39][C@@H:35]2[C@H:34]1/[CH:42]=[CH:43]/[C@H:44]([C:46]1[S:50][C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[CH:47]=1)[O:45][Si:10]([C:7]([CH3:9])([CH3:8])[CH3:6])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
A stirring mixture consisting of (3aR,4R,5R,6aS)-4-((R,E)-3-(benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (5a, limiting reagent) and imidazole (1.1 molar equivalents) in DMF (5 M in 5a) is cooled to 0° C. under a nitrogen atmosphere. A solution consisting of TBDPSCl (1.1 molar equivalents) in DMF is added slowly. Upon completion of the reaction, as judged by TLC, the reaction mixture is diluted with ethyl acetate and is washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 6a.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:14])[F:12])=[CH:10][C:2]=1[OH:1]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (5.0 g, 24.3 mmol) in dry DEE (150 ml), under nitrogen atmosphere, lithium aluminium hydride (1.11 g, 29.2 mmol) was added in portions. The reaction mixture was stirred for 12 h at ambient temperature and then quenched with water and NaOH (5 M). Aqueous HCl (10%) was added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (isooctane/EtOAc 1:1) to give the title compound (2.55 g). MS m/z (rel. intensity, 70 eV) 192 (M+, 32), 174 (45), 146 (bp), 145 (62), 96 (54).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:14])[C@H:11]([OH:13])[CH3:12].N1C(C)=CC(C)=CC=1C>ClCCl>[C:1]([O:14][CH2:10][C@H:11]([OH:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H](O)CO
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: C[C@@H](O)COC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Benzoyl chloride (10.98 mL, 94.62 mmol) was added dropwise to a solution of (R)-(−)-1,2-propanediol (6.00 g, 78.85 mmol) and 2,4,6-collidine (7.22 mL, 54.67 mmol) in 100 mL of anhydrous dichloromethane at −78° C. The reaction was stirred at −78° C. for three hours and at room temperature for 1 hr, before quenching with water (10 mL) for 15 minutes. The quenched mixture was washed with 0.5N HCl (4×50 mL) until the dark color diminished, and then with saturated NaHCO3 solution (4×50 mL) and brine. The organic layer was separated, dried over Na2SO4 and concentrated. Chromatography (silica gel 230-400 Mesh, 1:9 ethyl acetate/Hexane) of the residue afforded 8.9 g (63%) of (2R)-2-Hydroxypropyl benzoate as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (d, J=6.4 Hz, 3H), 3.93 (m, 1H), 4.10 (m, 2H), 4.95 (d, J=4.8 Hz, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.99 (d, J=6.8 Hz, 2H); MS (ESI) m/z 181 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[C:9]([NH:14][C:15](=O)[CH2:16][O:17][CH2:18][CH3:19])[CH:10]=[N:11]2)=[CH:6][CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:21]([CH2:22][C:23]([CH3:25])([OH:26])[CH3:24])[C:15]([CH2:16][O:17][CH2:18][CH3:19])=[N:14][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1
Reactant: CCOCC(=O)Nc1cnc2cc(Br)ccc2c1NCC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Yield: 49.3 %

Procedure:
A solution of sodium hydroxide (25 g, 0.625 mol) in water (205 mL) was added to a solution of N-[7-bromo-4-(2-hydroxy-2-methylpropylamino)quinolin-3-yl]-2-ethoxyacetamide (170.88 g, 0.431 mol) in ethanol (700 mL), and the reaction was heated at reflux under a nitrogen atmosphere for two hours. Upon cooling the reaction, a precipitate formed and was isolated by filtration. The solid was purified by flash column chromatography on silica gel (eluting sequentially with chloroform, 99:1 chloroform:methanol, and 97:3 chloroform:methanol) to provide 80.31 g of 1-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)n(-c2ccccc2)n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound. Yield: 50 mg (60%) of a cream colored solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:5][CH2:4]1.CO.CC[O:31]C(C)=O>>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N+:18]=2[O-:31])[CH2:5][CH2:4]1
Reactant: COC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Reactant: CCOC(C)=O
Solvent: CO
Product: COC1CCN(CCCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)CC1

Procedure:
H2O2 (70%, 0.92 mL, ca. 18.3 mmol) was added dropwise to a stirred solution of TFM (2.6 mL, 18.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 58 (655 mg, 1.8 mmol) and TFA (0.71 mL, 9.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 58 (360 mg, 55%) and (ii) 1,4-dioxide 59 (213 mg, 31%) as a red solid: mp (MeOH/EtOAc) 128-130° C.; 1H NMR δ 8.42 (br s, 1H, NH), 8.11 (s, 1H, H-9), 8.10 (s, 1H, H-5), 3.62-3.68 (m, 2H, CH2N), 3.28-3.36 (m, 4H, OCH3, CHO), 3.08 (dt, J=7.5, 1.1 Hz, 2H, H-6), 3.03 (dt, J=7.5, 1.1 Hz, 2H, H-8), 2.69-2.76 (m, 2H, CH2N), 2.55 (br t, J=6.2 Hz, 2H, CH2N), 2.26-2.34 (m, 2H, CH2N), 2.17 (p, J=7.5 Hz, 2H, H-7), 1.94-2.03 (m, 2H, CH2), 1.88 (p, J=6.2 Hz, 2H, CH2), 1.72-1.81 (m, 2H, CH2); 13C NMR δ 155.4, 149.5, 145.5, 138.1, 129.5, 115.7, 111.7, 75.8, 57.2, 55.4, 50.8 (2), 41.6, 33.3, 32.3, 30.3 (2), 25.5, 25.1. Anal. calcd for C19H27N5O3.H2O: C, 58.3; H, 7.5; N, 17.9. Found: C, 58.4; H, 6.8; N, 17.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][C:3]=1[CH3:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C2CCCN2)ccc1Cl
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(Cl)c(C)c2)cc1

Procedure:
The title compound, white solid, m.p. 103° C. and MS: m/e=349 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-chloro-3-methyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH2:26]([NH2:30])[CH:27]([CH3:29])[CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)CN
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC(C)C)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and isobutylamine as an off-white solid (82%). MS 402 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:28]([O:30][CH3:31])=[O:29].C([O-])([O-])=O.[K+].[K+]>COCCOC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([NH:1][C:28](=[O:29])[O:30][CH3:31])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:26][CH:25]=2)=[O:13])=[CH:16][CH:17]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)Nc1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
The product from Example 3 (500 mg, 1.45 mmol), methyl chloroformate (0.43 mL, 5.56 mmol), and K2CO3 (1.15 g, 8.33 mmol) were heated in DME (8 mL) at 65° C. for 24 hours. The mixture was allowed to cool to room temperature, concentrated under reduced pressure, and the residue was taken up in ethyl acetate (50 mL). The ethyl acetate was washed with H2O (3×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluant gradient from 99:1 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.15 (s, 1H), 8.53 (dd, J=4.5 Hz, 1.6 Hz, 1H), 8.02-8.05 (m, 2H), 7.88 (dd, J=8.1 Hz, 1.4 Hz, 1H), 7.70-7.77 (m, 4H), 7.35-7.46 (m, 3H), 3.55 (s, 3H), 1.29 (s, 9H); MS (ESI+) m/z 404 (M+H)+.