Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([C:11]1[CH:16]=[C:15]([S:17][CH3:18])[CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=[N:6]2.[OH-:21].[K+]>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][C:15]([S:17][CH3:18])=[CH:16][C:11]=1[C:5]1[N:4]=[C:3]2[C:7](=[N:8][CH:9]=[N:10][C:2]2=[O:21])[N:6]=1
Reactant: COc1ccc(SC)cc1-c1nc2ncnc(Cl)c2[nH]1
Reactant: [OH-]
Agent: [K+]
Product: COc1ccc(SC)cc1C1=NC2=NC=NC(=O)C2=N1

Procedure:
Prepared analogously to Example 16 from 6-chloro-8-(2-methoxy-5-methylmercapto-phenyl)-purine by reaction with 20% potassium hydroxide solution.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][CH2:41][S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:48][C:47]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[O:18][C:44](=[O:45])[C:43]=1[S:42][CH2:41][CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(OCCc2ccccc2)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(OCCc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-(2-phenylethoxy)-acetophenone (0.336 g, 1.40 mmol), lithium bis(trimethylsilyl)amide (0.257 g, 1.54 mmol), chlorotrimethylsilane (0.195 mL, 1.54 mmol), THF (15 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (0.417 g, 1.40 mmol). m.p. 104°-106° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.75 (t, 2 H), 2.97 (t, 2 H), 3.04 (t, 2 H), 4.25 (t, 2 H), 6.79 (s, 1 H), 7.25 (m, 14H), 11.95 (bs, 1 H).
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:41][CH2:42][O:43][CH3:44]>C(OCC)(=O)C>[CH3:44][O:43][CH2:42][CH2:41][N:15]1[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:14]1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1nc(-c2ccccc2)nc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
5-[2-Bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (96 mg, 247 μmol; example 22, step 1) and potassium carbonate (85.4 mg, 618 μmol) were combined with DMF (1 mL) and the mixture was stirred for 30 min at RT. 1-Bromo-2-methoxyethane (34.3 mg, 23.2 μL, 247 μmol) was added and the mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled down to RT, a second portion of 1-bromo-2-methoxyethane (34.3 mg, 23.2 μL, 247 μmol) and potassium carbonate (34.2 mg, 247 μmol) were added and the mixture was stirred at 60° C. for another 4 h. The reaction mixture was poured into ethyl acetate (25 mL) and the organic phase was washed with water (3×10 mL) and brine (1×15 mL). The aqueous layers were back-extracted with ethyl acetate (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to give 120 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless oil (29 mg, 83.7 μmol, 33.9%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)[CH3:5].[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33](O)=[O:34])=[C:31]([CH3:39])[N:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:34])=[C:31]([CH3:39])[N:30]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Reactant: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-pyridin-3-ylmethyl-amine (0.78 g, 2.12 mmol) was dissolved in DCM (10 mL). 6-Chloro-2,4-dimethyl-nicotinic acid (474 mg, 1.2 eq.), HOBT (430 mg, 1.5 eq.), DIPEA (760 μL, 2 eq.), and EDCI (612 mg, 1.5 eq.) were added sequentially. The mixture was stirred at room temperature for 6 h, and then quenched with saturated NaHCO3 (20 mL). The pH of the equilibrated aqueous was adjusted to 8 with 1N HCl, and the mixture was extracted with DCM (200 mL in 5 extracts). The combined organic was dried (Na2SO4) and concentrated. The residue was purified with flash chromatography on 150 mL silica using a gradient of 5%→10% MeOH in EtOAc containing 1% NH4OH as the eluent to give 6-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-pyridin-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (0.88 g, 77%) as light brown foam. 1H NMR (δ, CDCl3): 8.66 (1 H, d, br, J=5.7 Hz), 8.51 (1 H, s), 8.44 (1 H, d, J=4.8 Hz), 7.61 (1 H, d, J=8.1 Hz), 7.20 (1 H, dd, J=7.8, 4.8 Hz), 7.01 (1 H, s), 6.73 (2 H, d, J=9.0 Hz), 6.62 (2 H, d, J=9.0 Hz), 3.88 (2 H, s, an overlapping 1H, m), 3.71 (3 H, s), 3.33 (2 H, pentet, J=13.5 Hz), 2.80 (3 H, m), 2.51 (3 H, s, an overlapping 1 H, m), 2.30 (3 H, s), 2.12 (1 H, t, J=11.4 Hz), 1.82-1.66 (3 H, m), 1.60-1.46 (1 H, m), 1.11 (1 H, qd, J=12.3, 3.6 Hz), 0.99 (3 H, d, J=6.6 Hz), 0.92 (1 H, qd, J=12.0, 3.0 Hz); 13C NMR (δ, CDCl3): 167.2, 155.4, 152.9, 150.2, 148.9, 148.1, 147.5, 142.5, 135.7, 134.8, 123.3, 122.5, 117.8, 114.6, 60.5, 58.1, 55.6, 52.1, 47.5, 43.6, 40.1, 30.7, 29.4, 22.1, 18.8, 13.4; ES-MS m/z 536.5 (M+1). Anal. Calcd. for (C30H38N5ClO2) 0.2(H2O): C, 66.76; H, 7.17; N, 12.98; Cl, 6.57. Found: C, 66.80; H, 7.00; N, 12.86; Cl, 6.55.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](SC)=[N:7][C:6]=2[CH:12]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].N1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:19]3[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]3)=[N:7][C:6]=2[CH:12]=1
Reactant: CC(C)N1CCNCC1
Reactant: CSc1nc2cc(Br)ccc2s1
Solvent: c1ccncc1
Product: CC(C)N1CCN(c2nc3cc(Br)ccc3s2)CC1
Temperature: 160 °C
Yield: 76.3 %

Procedure:
A mixture of 5-bromo-2-(methylthio)benzothiazole (200 mg, 0.77 mmol), 1-isopropylpiperazine (985 mg, 7.7 mmol) and pyridine (610 mg, 7.7 mmol) was heated at 160° C. for 36 h. The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluent: 2% EtOAc in Petroleum ether) to give 200 mg (77%) of 5-bromo-2-(4-isopropylpiperazin-1-yl)benzothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Cl)cc1
Product: CCOC(=O)CCNc1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.116.1, starting from 4-chloroaniline and ethyl acrylate, ethyl N-(4-chlorophenyl)-3-aminopropionate was obtained as light tan oil.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH2:55][C@@H:56]([CH3:76])[C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:75])([O:72]CC)[O:69]CC)=[O:58]>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:55][C@@H:56]([CH3:76])[C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:69])([OH:72])[OH:75]
Reactant: CCOP(=O)(CCOCCOCCNC(=O)[C@H](C)N)OCC
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)N[C@@H](C)C(=O)NCCOCCOCCP(=O)(O)O)NC(=O)CCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2-dodecanamido-3-(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 26, step 8) and (S)-diethyl (2-(2-(2-(2-aminopropoxy)ethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 30, step 2) by following the procedure described for example 28, step 3-5. 1H NMR (DMSO-d6): δ 9.38 (br s, 1H), 8.14 (t, 2H), 4.18-4.25 (m, 1H), 3.92-4.00 (m, 1H), 3.06-3.67 (m, 15H), 2.92 (dd, 2H), 2.79 (dd, 2H), 2.59-2.73 (m, 4H), 2.07 (t, 2H), 1.65-1.75 (m, 2H), 1.42-1.50 (m, 4H), 1.21-1.28 (m, 35H), 0.85 (t, 6H). LRMS [M+H]=811.5.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CCNCCO
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and 2-Ethylamino-ethanol were converted to yield 2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol, MS: 405 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NN1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NN2CCOCC2)cn1
Yield: 60 %

Procedure:
As described for example 80c, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol), was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (62 mg, 60%) which was obtained as a white solid. MS: m/e=414.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][C:15]=1[C:20]([F:23])([F:21])[F:22])=[O:9]
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1ccc(Cl)cc1C(F)(F)F)c1cc(Cl)ccc1O
Yield: 21.5 %

Procedure:
Using 5-chlorosalicylic acid and 4-chloro-2-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:28]2=[O:30])=[CH:16][CH:17]=1
Reactant: OC(CNc1ccc(Br)cc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)CN1c1ccc(Br)cc1
Temperature: 0 °C
Yield: 151.2 %

Procedure:
A solution containing 2-(4-bromoanilino)-1-phenyl-1-ethanol (0.74 g, 0.00253 mol), N,N-diisopropylethylamine (1.01 g, 0.00786 mol) and N,N-dimethylaminopyridine (0.092 g, 0.00076 mol) in anhydrous dichloromethane (32 mL) was cooled to 0° C. and a solution of triphosgene (0.38 g, 0.00127 mol) in anhydrous dichloromethane (8 mL) was added dropwise. The reaction mixture was slowly warmed up to ambient temperature while stirring under an atmosphere of nitrogen for eighteen hours. The organic phase was washed with a saturated solution of sodium bicarbonate in water (40 mL), brine (30 mL) and dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (1:5) as mobile phase to yield 3-(4-bromophenyl)-5-phenyl-1,3-oxazolan-2-one (0.62 g, 0.00192 mol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](Cl)(Cl)=[S:14]>O>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)=[C:13]=[S:14]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Solvent: O
Product: O=C1CCc2ccc(N=C=S)cc2N1
Reaction time: 0.75 h

Procedure:
To a suspension containing 5,4 g of 7-amino-3,4-dihydro-2(1H)quinolone in 70 ml of water was added while stirring and cooling (0° C.) 4.0 ml of thiophosgene. Stirring was continued for 45 min at room temperature and product filtered and washed with water. Yield 5.8 g (87%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17]>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[N:6]([CH2:16][CH3:17])[CH:5]=[N:4][C:3]=1[C:7]#[N:8]
Reactant: N#Cc1nc[nH]c1N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cnc(C#N)c1N
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution/suspension of 5-amino-1H-imidazole-4-carbonitrile (2.16 g) in tetrahydrofuran/N,N-dimethylformamide under an atmosphere of nitrogen was added potassium carbonate (3.3 g) and iodoethane (1.9 mL). The reaction mixture was stirred at room temperature for 60 hours, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 2-5% methanol in dichloromethane afforded the title compound as an off-white solid (0.60 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:20])=[O:19]
Reactant: OCCc1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1cccnc1

Procedure:
The 2-(3-pyridyl)ethan-1-ol (Maybridge, 0.15 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5](OS(C(F)(F)F)(=O)=O)[CH2:6][N:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[S:8]([CH3:11])(=[O:10])=[O:9])=[O:4].[CH3:37][NH:38][CH2:39][CH2:40][CH2:41][Cl:42]>C(Cl)Cl>[Cl:42][CH2:41][CH2:40][CH2:39][N:38]([C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][N:7]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)[S:8]([CH3:11])(=[O:9])=[O:10])[CH3:37]
Reactant: CNCCCCl
Reactant: COC(=O)[C@@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)N(C)CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of N-[(2R)-2-methoxycarbonyl-2-trifluoromethanesulfonyloxyethyl]-N-[4-(4-trifluoromethylphenoxy)phenyl]methanesulfonamide (565 mg, 1.0 mmol) from Step C in dried CH2Cl2 (2 mL) at 0° C. under N2 was added N-methyl-3-chloropropyl-amine (ca. 1.0 M in CH2Cl2, 4.0 mL, 4.0 mmol) dropwise. The mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was directly concentrated to give a crude mixture, which was purified by silica gel chromatography using EtOAc/hexane (1/4 to 1/1) as the eluent to give 455 mg of the product (81%) as a sticky oil. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 7.12-7.04 (m, 4H), 3.96-3.90 (m, 2H), 3.69 (s, 3H), 3.59-3.54 (m, 2H), 3.47 (t, J=7.5 Hz, 1H), 2.94 (s, 3H), 2.75-2.55 (m 2H), 2.27 (s, 3H), 1.90-1.83 (m, 2H); MS (EI) 522 (M++1, 100).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:27]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]([C:12](=[O:21])[CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[C:8](=[S:30])[NH:7][C:6]=2[CH:27]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2NC(=O)c2cccnc21
Solvent: c1ccncc1
Product: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 8,9-dimethyl-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dimethyl-6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH2:23][Br:32])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1cn([C@H]2CC[C@@H](COO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CBr)c(=O)[nH]c2=O)O1

Procedure:
A solution of 5′-O-TBDMS-3′-deoxythymidine (2) (700 mg, 2.055 mmol) in CCl4 (50 mL) was treated with NBS (702 mg, 4.11 mmol), followed by irradiation from a flood lamp (150 W) under reflux for 3 h to give (3). After filtering the solid, the filtrate was evaporated to dryness, followed by coevaporating with THF (20 mL×3). To a stirred solution of the 3-(trifluoroacetamido)prop-1-yne (620 mg, 4.11 mmol), DBU (0.61 mL, 4.11 mmol) and CuI (782 mg, 4.11 mmol) in THF (20 mL) was added a solution of 3 (Need conc. and solvent), followed by stirring at r.t for 15 h. After evaporating solvent, the residue was purified by silica gel column chromatography with MeOH:CH2Cl2 (0-4%) to afford 17 (170 mg, 0.35 mmol, 17%) over two steps. 1H NMR (CDCl3), 300 MHz) δ 9.55 (br s, 1H, NH), 7.74 (s, 1H, H6), 7.18 (br s, 1H, NH), 6.04 (dd, 1H, H1′, J=3.9 and 6.3 Hz), 4.23-4.10 (m, 3H, H4′ and CH2), 3.94 (dd, 1H, H5′, J=3.3 and 11.4 Hz), 3.75 (dd, 1H, H5′, J=3.6 and 11.4 Hz), 3.26-3.22 (m, 2H, 2 CH2), 2.45-2.35 (m, 1H, H2′), 2.09-1.85 (m, 3H, H2′, 2H3′), 0.90 (d, 9H, 3 CH3), 0.09 (s, 6H, 2 CH3). 19F NMR (CDCl3, 282.2 MHz) δ −76.22 (s, CF3).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl.O>C(O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: COC(=O)Cc1cccc(NS(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Methyl 3-(methanesulfonylamino)phenylacetate (3.36 g, 13.8 mmol) was dissolved in ethanol (16 mL) and 1N NaOH (30 mL) added. The reaction was stirred for 1 hour, then 1N HCl (50 mL) and water (50 mL) were added. The product was extracted into ethyl acetate (3×50 mL) and the combined extracts were washed with water and brine and dried (MgSO4). Removal of solvent afforded 3-(methanesulfonylamino)phenylacetic acid (2.90 g, 92%). 1H NMR (DMSO-6) δ 12.32 (1H, br), 9.69 (1H, br), 7.26 (1H, dd), 7.10 (2H, m), 7.00 (1H, d), 6.57 (1H, s), 3.54 (2H, s), 2.97 (3H, s).
Reaction SMILES: [OH:1][C:2]1[C:11](S([O-])(=O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16]([O-:19])(=[O:18])=[O:17])[CH:8]=2)[CH:3]=1.[Na+].[Na+].[OH-:22].[Na+]>O>[OH:1][C:2]1[C:11]([OH:22])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16]([OH:19])(=[O:18])=[O:17])[CH:8]=2)[CH:3]=1
Reactant: [OH-]
Reactant: O=S(=O)([O-])c1ccc2cc(O)c(S(=O)(=O)[O-])cc2c1
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(O)c(O)cc2c1
Yield: 96.3 %

Procedure:
Disodium 2-hydroxynaphthalene-3,6-disulfonate (348 g) was added to 176 g of a 50% aqueous solution of sodium hydroxide, and the mixture was stirred. Then, 900 g of a hydrogenated triphenyl mixture was mixed, and the resulting mixture was dehydrated. The dehydrated mixture was reacted at 270° C. for 1.5 hours in a nitrogen stream. After cooling, 2 liters of water was added to the reaction mixture to separate the reaction medium layer. The aqueous layer was decolorized with activated carbon, and then precipitated with an acid to give 231 g (yield 96.3%) of 2,3-dihydroxynaphthalene-6-sulfonic acid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:10]([NH:11][CH3:12])=[C:9]([I:18])[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.CCO.[Sn](Cl)Cl>[OH-].[Na+]>[CH3:1][C:2]1[C:6]([C:7]2[CH:14]=[C:13]([NH2:15])[C:10]([NH:11][CH3:12])=[C:9]([I:18])[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: CNc1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1c(N)cc(-c2c(C)noc2C)cc1I
Temperature: 110 °C

Procedure:
Into a microwave vial containing 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (610 mg, 1.64 mmol, 1 equiv) is added EtOH (12 mL, 0.25M) and tin (II) chloride (622 mg, 3.28 mmol, 2 equiv). The reaction was heated for 30 min at 110° C. The reaction was then stirred in 2N NaOH solution for 20 minutes before being partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by flash column chromatography to furnish 4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine.