Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1N=C(C2C(C3C=C(NC(=O)C4C=C(F)C=CC=4F)C=CC=3)=NN3C=CC=CC=23)C=CN=1.[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([NH:42][C:43]2[N:48]=[C:47]([C:49]3[C:50]([C:58]4[CH:59]=[C:60]([NH:64][C:65](=[O:74])[C:66]5[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=5[F:73])[CH:61]=[CH:62][CH:63]=4)=[N:51][N:52]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=34)[CH:46]=[CH:45][N:44]=2)[CH:39]=[CH:40][CH:41]=1>CC(O)C.Cl.CCOC(C)=O>[F:73][C:67]1[CH:68]=[CH:69][CH:70]=[C:71]([F:72])[C:66]=1[C:65]([NH:64][C:60]1[CH:61]=[CH:62][CH:63]=[C:58]([C:50]2[C:49]([C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][CH3:2])[CH:37]=4)[N:48]=3)=[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][N:52]3[N:51]=2)[CH:59]=1)=[O:74]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Reactant: NCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 72.8 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,5-difluorobenzamide (100 mg, 0.22 mmol) (prepared according to a procedure similar to that described in Example 43, Step A) and N-[(3-aminophenyl)methyl]-2,2,2-trifluoroacetamide (59 mg, 0.27 mmol) (prepared as described in Example 180) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The mixture was heated to 180° C. in a microwave for 15 min. The reaction mixture was diluted with 25 mL EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and purified by flash chromatography to give the title compound (90 mg, 64% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.64 (s, 1H), 9.99 (t, J=5.7 Hz, 1H), 9.63 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.42-7.55 (m, 5H), 7.35 (d, J=7.5 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.14 (t, J=6.8 Hz, 4H), 6.85 (d, J=7.3 Hz, 1H), 6.54 (d, J=5.1 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H). MS (ESI) m/z=645 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH:4][C:5]1[CH:6]=[C:7]([C:13](=[O:19])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=[C:9]([NH:11][CH3:12])[CH:10]=1>C(O)C>[CH3:3][NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([NH:11][CH3:12])[CH:10]=1)[CH:13]([OH:19])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CNc1cc(NC)cc(C(=O)CS(C)(=O)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1cc(NC)cc(C(O)CS(C)(=O)=O)c1

Procedure:
A suspension of 7.6 g. of sodium borohydride and 12.8 g. of 3',5'-bis-(methylamino)-2-methylsulfonylacetophenone in 200 ml. of ethanol was stirred for 18 hours at 25° C. After the addition of 50 ml. of water, the solution was evaporated to dryness in vacuo. The residue was heated to boiling in 300 ml. of ethyl acetate. The insoluble material was separated and the filtrate evaporated to dryness in vacuo. Recrystallization of the residue from ethanol gave 3,5-bis(methylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, having a melting point of 106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:13][C:14]1[C:15]([OH:54])=[C:16]([S:21]([N:24]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:25][C:26]2[CH:31]=[C:30]([CH2:32][NH:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:29]=[C:28]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:27]=2)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.CCN(CC)CC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:13][C:14]1[C:15]([OH:54])=[C:16]([S:21]([N:24]([CH2:25][C:26]2[CH:27]=[C:28]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:29]=[C:30]([CH2:32][N:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])[CH:31]=2)[CH2:46][C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(C)CNCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(Cc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 3,5-dichlorobenzenesulfonyl chloride (27.0 mg, 0.11 mmol) in CH2Cl2 (3 mL) was added 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-(4-fluorophenoxy)-5-((isobutylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (70 mg, 0.11 mmol, 80% purity), followed by the addition of Et3N (0.09 mL, 0.66 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with CH2Cl2 and saturated NaHCO3 solution. The organic layer was concentrated. To the residue was added 1 N NaOH/MeOH/THF. The resulting mixture was left for 2 h. The mixture was concentrated and the residue was diluted with CH2Cl2 and water. The organic layer was concentrated. The residue was dissolved in MODEL and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give a white solid (35 mg, 38%). 1H NMR (CD3OD): δ 7.67-7.63 (m, 4H), 7.57 (d, J=2.8 Hz, 1H), 7.14-7.04 (m, 4H), 6.91 (t, J=8.8 Hz, 2H), 6.87-6.83 (m, 2H), 6.70 (s, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 4.21 (s, 2H), 2.91 (d, J=7.6 Hz, 2H), 1.65 (m, 1H), 0.74 (d, J=6.4 Hz, 6H); MS (ESI): (M−H)−=843.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:21][N:20]=1>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[CH:23]=2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(-c2cc(CCl)no2)cc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccc(F)cc2)on1

Procedure:
Synthesized in a manner similar to Example 23 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(4-fluorophenyl)isoxazole: MS (ES) m/z 400 (M+1).
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:44][C:45]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:46])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2CO3 (3.5 g, 40 mmol) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3OH in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1.[N:30]#[C:31]Br.C(OCC)(=O)C>CO.ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]5[N:28]=[C:31]([NH2:30])[NH:29][C:24]=5[CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccc3c(c2)CN(c2ccnc4ccccc24)CCO3)cc1N
Reactant: N#CBr
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a solution of 4-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-benzene-1,2-diamine (90 mg, 0.14 mmol, synthesized according to the method of example 2) in methanol (1 mL) was added a 3M solution of cyanogen bromide in dichloromethane (0.10 mL), and the reaction mixture was stirred at room temperature for 8 d. During this time additional cyanogen bromide was added after 1 d (0.10 mL), 2 d (0.20 mL), 3 d (0.20 mL), and 4 d (0.20 mL) reaction time. Ethyl acetate (50 mL) was added, and the solution was washed with 0.5N aqueous sodium hydroxide (2×50 mL), water (50 mL), and brine (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title Compound as the acetate salt (8 mg, 7% yield) as an off-white solid. 1H NMR (400 MHz, methanol-d4): 8.54 (d, 1H), 8.14 (d, 1H), 7.94 (d, 1H), 7.73 (m, 1H), 7.60-7.47 (m, 4H), 7.38 (m, 1H), 7.31 (d, 1H), 7.10 (d, 1H), 7.07 (d, 1H), 4.70 (s, 2H), 4.41 (m, 2H), 3.93 (m, 2H), 1.94 (s, 3H); MS (EI) for C25H21N5O: 408 (MH+).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[C:15]([C:20]2[O:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][N:24]=2)[C:16]([NH2:19])=[N:17][CH:18]=1)(=O)=[O:5])([CH3:3])[CH3:2].ClC1C=C(C(OO)=O)C=CC=1>ClCCl>[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]=[C:15]([C:20]2[O:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:23][N:24]=2)[C:16]([NH2:19])=[N:17][CH:18]=1)=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)S(=O)c1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
5-(2-isopropylsulfonylphenyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (50 mg, 0.1284 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. in an ice-bath. 3-Chlorobenzenecarboperoxoic acid (26.59 mg, 0.1541 mmol) was added in one portion with rapid stirring. The mixture was stirred at 0° C. for 15 min, washed with saturated aqueous NaHCO3 solution (1×5 mL) and brine (1×5 mL), dried over MgSO4 and concentrated in vacuo to leave a solid which was purified by column chromatography on silica eluting with ether/petroleum ether to yield the product as a yellow solid (16.1 mg, 31% yield); 1H NMR (400.0 MHz, CDCl3) d 1.2 (d, 3H), 1.35 (d, 3H), 3.5-3.6 (m, 1H), 7.5-7.75 (m, 2H), 7.5-7.65 (m, 7H), 8.25 (d, 2H) and 8.55 (s, 1H) ppm; MS (ES+) 406.1
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=O.NC1C(=S)NC=CC=1>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]1[S:17][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([C:8]1([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]1)[N:4]=2
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Nc1ccc[nH]c1=S
Product: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (27.3 mg, 113 μmol) and 2,4-difluorobenzoyl chloride (13.8 μl, 113 μmol) according to Reference V and the general procedure for the condensation of 3-aminopyridine-2-thione with aryl acid chlorides to give 2-(2,4-difluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 364.1; Observed: 365.0 (M++1).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:22][O:1][C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccccc1Oc1cccc(C=O)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
2-Hydroxy-3-(o-tolyloxy)benzaldehyde (64.20 g), dimethyl sulfate (46.10 g) and powdered potassium carbonate (50.50 g) were added to dimethylformamide (150 ml) and stirred at room temperature for 2 hrs. The reaction mixture was poured into water (1 l), and the precipitating crystals were collected by filtration. The aqueous filtrate was extracted with diethyl ether, and the crystals obtained above were dissolved in the extract. The ether solution was washed with water, dried over magnesium sulfate and evaporated. The crystalline residue was recrystallized from methanol to give colorless crystals of 2-methoxy-3-(o-tolyloxy)benzaldehyde (48.70 g). mp 53°-55° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+].C([O-])=O>CO>[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCCc2cc(-c3csc(N4CCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 60 mg (0.16 mmol) of 1-[4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 22 μl (0.16 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 2N NaOH solution in methanol. The product is in the form of the formate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:18]=[C:19](O)[CH:20]=[N:21][CH:22]=1.C(N(CC)CC)C.CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)(=[O:5])=[O:4]
Reactant: Oc1cncc(Cl)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58.9 %

Procedure:
Trifluoromethanesulfonic anhydride (5.0 mL, 30 mmol) was dissolved in CH2Cl2 (100 mL), and cooled to 0° C. 5-Chloro-3-pyridinol (3.10 g, 23.9 mmol), and triethylamine (6.5 mL, 47 mmol) were dissolved in CH2Cl2 (50 mL), and the resulting solution was added to the cold trifluoromethanesulfonic anhydride solution dropwise via cannula. The resulting dark brownish-red solution was stirred at 0° C. for 5 minutes, and then the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring for 16 h at ambient temperature the reaction was quenched by pouring into water and basified by addition of saturated aqueous sodium carbonate. The basic aqueous phase was extracted with CH2Cl2 (2.times.50 mL), the combined organics dried over Na2SO4, filtered and concentrated in vacuo. The resulting black viscous oil was filtered through a plug of silica gel and fractions were collected while eluting with 1:1 hexane:ethyl acetate. Fractions containing the desired product were combined, concentrated in vacuo, and further purified by column chromatography eluting with 15:1 then 10:1 hexane:ethyl acetate to afford 5-chloro-3-pyridinyl trifluoromethanesulfonate (3.68 g, 59% yield) as a golden liquid. 1H NMR (CDCl3, 300 MHz) Δ8.65 (d, J=2 Hz, 1H), 8.52 (d, J=2 Hz, 1H), 7.70 (t, J=3 Hz, 1H). MS (ESI) 261 (M+, 35Cl), 263 (M+, 37Cl).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])=[O:3].[C:12]1([O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(OCCO)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][CH:20]([OH:22])[CH2:19][O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: c1ccc(OCC2CO2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOCCO
Product: CC(=O)c1ccc(OCC(O)COc2ccccc2)cc1O
Reaction time: 48 h

Procedure:
A solution of resacetophenone (15.2 g), phenylglycidyl ether (15.0 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution) in 2-ethoxyethanol (75 ml) was heated under reflux for 2 days. Removal of solvent under reduced pressure yielded a dark, viscous oil, which was allowed to stand for 48 hours, by which time it had crystallized to a solid mass. This was triturated with a mixture of ether and light petroleum (b.p. 40°-60°.), filtered, washed with a little more ether-petroleum and dried. Crystallization from methanol gave 1-(4-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-phenoxypropane as a greyish-white solid, 9.0 g, m.p. 63°-65°.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH:17]=1.Cl>[Pd]>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]1
Reactant: COC(=O)N1CC=C(c2cccc(S(C)(=O)=O)c2F)CC1
Agent: [Pd]
Agent: Cl
Product: COC(=O)N1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to preparation 18: Methyl 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (1.45 g, 4.6 mmol), palladium on carbon (0.2 g) and hydrochloric acid (0.5 ml, conc). Yield: 0.76 g. MS m/z (relative intensity, 70 eV) 315 (M+, 41), 256 (bp), 236 (54), 141 (43) 114 (50).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH:21]([CH3:23])[CH3:22])=[C:4]([C:15]([O:17]CC)=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7].[OH-].[Na+].P(=O)(O)(O)O>CO>[Br:1][C:2]1[C:3]([O:20][CH:21]([CH3:23])[CH3:22])=[C:4]([C:15]([OH:17])=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[Br:7]
Reactant: CCOC(=O)c1c(OC(C)C)c(Br)c(Br)n1Cc1ccccc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1c(Br)c(Br)n(Cc2ccccc2)c1C(=O)O
Temperature: 0 °C
Yield: 87.9 %

Procedure:
Ethyl 4,5-dibromo-3-(1-methylethoxy)-1-(phenylmethyl)-1H-pyrrole-2-carboxylate (2.5 g, 0.006 moles) is dissolved in methanol (30 mL), and 2N NaOH (15 mL) is added. The mixture is heated under nitrogen to reflux. After 1 hour the mixture is stirred into ice water (350 mL) and acidified with phosphoric acid. The precipitate is filtered off, rinsed with cold dilute acid, ice water and dried to afford the pure product (2.2 g); mp 122° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[C:28]([NH:31][C:32](=[O:34])[CH3:33])[CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[C:28]([NH:31][C:32](=[O:34])[CH3:33])[CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cn1)C(C)Oc1cc(Cl)ccc1-2
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: CC(=O)Nc1cc2c(cn1)C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Yield: 33 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford tert-butyl((2S)-1-((2-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (290 mg, 0.617 mmol, 33% yield) as a yellow oil. LCMS (ESI) m/e 470.3 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method F): tR=0.99 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].C(N(CC)CC)C.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nc2ccccc2s1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(CSc2nc3ccccc3s2)cc1

Procedure:
To a solution of 2-benzothiazolthiol (250 g) in N,N-dimethylformamide (1 l) was added triethylamine (208 ml) under ice-cooling and dropwise a solution of benzyl bromide (178 ml) in N,N-dimethylformamide (300 ml) and the mixture was stirred for 40 minutes. The resulting solution was poured into water (10 l) and the formed precipitate was separated by filtration and dissolved in dichloromethane (3 l). After drying over anhydorpus magnesium sulfate, dichloromethane was removed in vacuo to give 378 g of the objective compound.
Reaction SMILES: [C:1]([CH2:6][C:7](Cl)=[O:8])([O:3][CH2:4][CH3:5])=[O:2].[CH2:10]([NH2:12])[CH3:11]>C1C=CC=CC=1>[CH2:10]([NH:12][C:7](=[O:8])[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH3:11]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCN
Solvent: c1ccccc1
Product: CCNC(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 15.0 g. (0.1 mole) of carboethoxyacetyl chloride in 150 ml. of benzene is added, with cooling, 9.9 g. (0.22 mole) of ethylamine in 50 ml. of the same solvent. The reaction mixture is allowed to stir at room temperature overnight, followed by filtration. The filtrate is washed with water, dried over sodium sulfate and concentrated to dryness. The residual product is washed several times with diisopropyl ether and dried in vacuo. The crude product is employed in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]([CH:13]2[CH2:15][CH2:14]2)=O)[C:9]#[N:10])=[CH:4][CH:3]=1.O.[NH2:17][NH2:18].C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:11]([CH:13]3[CH2:14][CH2:15]3)=[N:17][NH:18][C:9]=2[NH2:10])=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#CC(C(=O)C1CC1)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1[nH]nc(C2CC2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenyl)-3-cyclopropyl-3-oxopropanenitrile(7.74 g), hydrazine hydrate (3.5 mL) and acetic acid (7.5 mL) are dissolved in a toluene solvent and stirred for 16 hours while heating. Upon completion of reaction, after cooling to room temperature, the solvent is removed by distillation under reduced pressure. The remainder is extracted with water and ethyl acetate. The extracted organic layer is dehydrated and distilled under reduced pressure. The remainder is purified by column chromatography to yield 5.2 g of the target compound. 1H NMR (CDCl3, 300 MHz): δ 7.40 (m, 4H), 3.75 (br, 2H), 1.86 (m, 1H) 0.93 (m, 2H), 0.65 (m, 2H).