Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32]C)=[C:6]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([C:26]([F:27])([F:28])[F:29])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[N:18]3)[CH:7]=1
Reactant: COc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Reaction time: 15 h
Yield: 76.8 %

Procedure:
100 mg (0.21 mmol) of 4-(5-fluoro-2-methoxyphenyl)-1-(2-methoxyquinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 9 ml of CH2Cl2 is mixed at room temperature with 4 ml of 1M boron tribromide-CH2Cl2 solution. After 15 hours at room temperature, the batch is poured into saturated NaHCO3 solution, stirred for 10 minutes and extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Chromatography on silica gel with hexane/ethyl acetate yields 73 mg of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A 250 ml two-necked round-bottomed flask equipped with a magnetic bar, a thermometer and a reflux condenser is charged with DMF (30 ml), 4-chloro-3-trifluoromethyl-phenol (4.5 g), 2-chloro-4-methyl-5-nitro-pyridine (4.0 g) and potassium carbonate (6.4 g). The reaction mixture is stirred at ambient temperature for 1 hour, poured into water (300 ml), acidified with HCl 5 molar (15 ml) and then extracted with ethylacetate (4×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 7:3 (v:v) gives 7.03 g of the compound as a red solid (MP: 75-80° C.).
Reaction SMILES: C(N(CC)CC)C.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18].CS(O[CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:45]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:46][C@H:47]([OH:59])[C:48]2[C:56]3[S:55][C:54](=[O:57])[NH:53][C:52]=3[C:51]([OH:58])=[CH:50][CH:49]=2)=[CH:40][CH:39]=1)(=O)=O>C(#N)C>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]([N:19]1[CH2:24][C:23]2([CH2:29][CH2:28][N:27]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[CH:40][C:41]([CH2:44][N:45]([CH2:46][C@H:47]([OH:59])[C:48]4[C:56]5[S:55][C:54](=[O:57])[NH:53][C:52]=5[C:51]([OH:58])=[CH:50][CH:49]=4)[C:60](=[O:61])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[CH:42][CH:43]=3)[CH2:26][CH2:25]2)[O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2nc4ccccc4s2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C

Procedure:
Triethylamine (0.25 mL) was added to a solution of benzo[d]thiazol-2-yl(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 106, step b) (0.22 g) in acetonitrile (2.5 mL). This solution was added to a solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.5 g) in acetonitrile (2.5 mL). The resulting mixture was heated at 80° C. for 48 hours. The reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a cream foam. Yield 0.34 g.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:23])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:24]([S-:26])#[N:25].[K+].[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CC(O)=O>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]2[N:22]=[C:24]([NH2:25])[S:26][C:17]=2[C:16]=1[Br:23])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: N#C[S-]
Reactant: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2nc(N)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a solution of freshly prepared (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (7 g, 18.1 mmol) in HOAc (90 mL) was added KSCN (1.76 g, 18.1 mmol) at r.t. The reaction mixture was stirred at r.t. for 0.5 h. Pyridinium perbromide (5.79 g, 18.1 mmol) was added slowly over a period of 10 min, and stirred at r.t for 2 h. The mixture was alkalized to pH=8 using saturated aqueous NaHCO3 solution, then extracted with EtOAc (3×600 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column (Petroleum Ether:EtOAc (10:1→5:1)) to afford (S)-2-(2-amino-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (2.74 g, 34.3%) as yellow solid. LCMS-ESI+: calc'd for C19H27BrN2O3S: 443.1 and 445.1 (M+H+); found: 443.1 and 445.1 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.15 (s, 1H), 5.53-5.49 (m, 1H), 4.31-4.26 (m, 1H), 4.17-4.13 (m, 1H), 2.64 (s, 3H), 1.15 (s, 9H), 1.11 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: BrCc1ccccn1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccccn2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-pyridine following the procedure of Example 478: MS (ESI) m/z 485.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([CH:33]1[CH2:36][CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: NC(=NO)C1CCC1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CCC3)no2)C1

Procedure:
150 mg (0.373 mmol) of the compound from Example 44A and 85 mg (0.746 mmol) of N′-hydroxycyclobutanecarboximidamide were reacted according to the General Method 2. Yield: 58 mg (48% of theory)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(=O)C(F)(F)F)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[Na+].Cl>O>[NH:17]1[CH2:18][CH2:19][CH2:20][CH:16]1[C:13]1[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:8])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(N1CCCC1c1ccc(S(=O)(=O)Nc2nccs2)cc1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(Nc1nccs1)c1ccc(C2CCCN2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
Synthesized according to general procedure 38. A solution of N-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzenesulfonamide (750 mg, 1.8 mmol), NaOH (221 mg, 5.5 mmol), and H2O (2.5 mL) was stirred at RT for 1 h, then cooled to 0° C. Hydrochloric acid (0.45 mL, 5.5 mmol) was added, and the reaction was stirred at 0° C. for 20 min. The formed precipitate was filtered off and dried under vacuum to give 4-(pyrrolidin-2-yl)-N-(thiazol-2-yl)benzenesulfonamide (300 mg, 53%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=310.3; tR=0.44 min.
Reaction SMILES: [N+](C1C=CC(C[C:9]23[CH2:15][C:14](=[O:16])[N:13]2[C:12]([C:17]([O-:19])=[O:18])=[C:11]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:10]3)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:33]>O1CCOCC1.O.[Pd]>[O:16]=[C:14]1[N:13]2[CH:9]([S:10][C:11]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]2[C:17]([O-:19])=[O:18])[CH2:15]1.[Na+:33]
Reactant: O=C([O-])C1=C(Oc2ccccc2)SC2(Cc3ccc([N+](=O)[O-])cc3)CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C1=C(Oc2ccccc2)SC2CC(=O)N12
Yield: 74.6 %

Procedure:
A mixture of a solution of 56 mg of 4-nitrobenzyl-7-oxo-3-phenoxy-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in 3 ml of dioxan and 12.5 mg of sodium bicarbonate in 2 ml of water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 90 minutes. The mixture was then filtered through Celite, and lyophilized to yield 30 mg of the title compound as a pale yellow crystalline solid.
Reaction SMILES: [N+]1([O-:7])C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([N:27]2[CH2:31][C@H:30]([CH2:32][N:33]3[CH:37]=[CH:36][N:35]=[N:34]3)[O:29][C:28]2=[O:38])[CH:12]=[CH:13][C:14]=1[C:15]1[CH:16]=[N:17][C:18]([C:21]2[N:22]=[N:23][N:24]([CH3:26])[N:25]=2)=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C1(P([Pd-4](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)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([N:27]2[CH2:31][C@H:30]([CH2:32][N:33]3[CH:37]=[CH:36][N:35]=[N:34]3)[O:29][C:28]2=[O:38])[CH:12]=[CH:13][C:14]=1[C:15]1[CH:16]=[N+:17]([O-:7])[C:18]([C:21]2[N:22]=[N:23][N:24]([CH3:26])[N:25]=2)=[CH:19][CH:20]=1
Reactant: [O-][n+]1ccccc1
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)n1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)c[n+]2[O-])n1
Temperature: 75 °C

Procedure:
The above sample of pyridine oxide was combined with (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (335 mg, 0.86 mMol, prepared as in Example 1), potassium carbonate (400 mg, 2.9 mMol), and tetrakis(triphenylphosphino)palladium(0) (80 mg, 0.07 mMol) and suspended in THF (10 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then diluted with water. The precipitated solids were collected on a filter, rinsed with water, ether and 1:1 methylene chloride:hexane and dried in vacuo to give the pure product as an off-white solid, 134 mg.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][NH:14][C:13]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][N:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:19])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C(=O)CCNC1=O
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)CCN(c2ccccc2)C1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.35 mmol), from this Example step 1, bromobenzene (0.037 mL, 0.35 mmol), tris(dibenzylideneacetone)dipalladium (6.4 mg, 0.01 mmol), Xanthphos (0.0121 g, 0.021 mmol) and Cs2CO3 (0.171 g, 0.52 mmol) were combined in dry dioxane (1 mL) and stirred at 100° C. overnight in a sealed tube. The reaction mixture was partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over Na2SO4 and the solvent evaporated in vacuo. The product was purified by preparative TLC using ethyl acetate and hexane (30:70) to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:16]=[N:17][CH:18]=2)=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccc(-n3cncc3-c3ccncc3)cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(-n2cncc2-c2ccncc2)cc1
Temperature: 75 °C
Yield: 88 %

Procedure:
A solution of Preparation 81 (4-(1-(4-(benzyloxy)phenyl)-1H-imidazol-5-yl)pyridine, 2 g, 6.1 mmol) and anisole (13 mL, 122 mmol) in trifluoracetic acid (50 mL) was heated at 75° C. for 24 h. The solvent was removed in vacuo and the residue was purified via silica gel chromatography with chloroform-methanol-ammonium hydroxide (94:5:1) to afford 1.27 g (88%) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 158.402, 149.145, 141.061, 138.018, 120.600, 129.822, 127.482, 127.370, 121.933, 116.497; MS (AP/CI) 238.3 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH:37]([NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH:37]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[NH:45][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1cccc(Cl)c1

Procedure:
(2-(3-Chloro-phenyl)-2-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 4 supra) by following the method in Example 61.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:9][N:10]([CH2:12][CH2:13]O)[CH3:11]>>[C:1]([O:8][CH2:13][CH2:12][N:10]([CH3:11])[CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][CH2:13][CH2:12][N:10]([CH3:11])[CH3:9])=[O:5]
Reactant: CN(C)CCO
Reactant: O=C(O)CCC(=O)O
Product: CN(C)CCOC(=O)CCC(=O)OCCN(C)C

Procedure:
In method I succinic acid is reacted with dimethylaminoethanol to give bis(2-dimethylaminoethyl) succinate, which is then reacted with methyl chloride to give succinylcholine chloride.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([S:29](O)(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH3:52][NH:53][CH3:54]>ClCCl.CN(C=O)C.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([S:29](=[O:31])(=[O:30])[N:53]([CH3:54])[CH3:52])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH3:41])=[O:15])[CH:4]=[C:3]([C:2]([F:45])([F:1])[F:44])[CH:8]=1
Reactant: CNC
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(S(=O)(=O)O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCC(S(=O)(=O)N(C)C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 0.13 g (0.19 mmol) 5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-sulfonic acid in 2 ml dichloromethane were added 0.33 ml (0.39 mmol) oxalyl chloride and one drop of DMF at 0° C. After 30 min the reaction mixture was allowed to warm to room temperature during 2 h. To the yellow reaction mixture were added 1.8 ml (20 mmol) of an aqueous solution of dimethylamine (60%). After 1 h the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 92 mg (69%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([NH2:11])=[NH:10])=[C:4]([F:12])[CH:3]=1.O=[C:14]1[CH2:18][S:17][CH2:16][CH:15]1[C:19](OCC)=[O:20].C[O-].[Na+]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:11][C:14]3[CH2:18][S:17][CH2:16][C:15]=3[C:19](=[O:20])[N:10]=2)=[C:4]([F:12])[CH:3]=1
Reactant: N=C(N)c1cc(F)c(Cl)cc1F
Reactant: CCOC(=O)C1CSCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2c1CSC2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-2,5-difluorobenzenecarboxamidine, ethyl 4-oxotetrahydrothiophene-3-carboxylate, NaOMe, and MeOH was stirred at ambient temperature for 19 hours and then at 60° C. for 5 hours to yield 2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4(1H)-one.
Reaction SMILES: N1C=CC=[CH:3][C:2]1=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[CH:25][CH:24]=3)[C:19](=[O:36])[CH:18]=2)=[N:13][CH:14]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[CH2:2][CH3:3])=[CH:25][CH:24]=3)[C:19](=[O:36])[CH:18]=2)=[N:13][CH:14]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OC[C@@H]2CCCN2)cc1
Reactant: O=c1cccc[nH]1
Product: CCN1CCC[C@H]1COc1ccc(-n2ccc(OCc3ccc(Cl)cn3)cc2=O)cc1

Procedure:
Example 123 was repeated except that 4-[(5-chloro-2-pyridinyl)methoxy]-1-4-{(3R)-3-pyrrolidinyl]oxy}phenyl)-2H-pyridin-2-one was replaced with 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(2S)-2-pyrrolidinyl]methoxy}phenyl)-1H-pyridin-2-one, to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=O.B.CSC.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH:10][CH2:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: COC(=O)c1cccnc1NC(=O)c1ccnc(Cl)c1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1NCc1ccnc(Cl)c1
Yield: 19.9 %

Procedure:
A stirred solution of 2-[(2-chloro-pyridine-4-carbonyl)-amino]-nicotinic acid methyl ester (4 g, 13.72 mmol) in dry THF (60 mL), under nitrogen, was treated with borane-dimethyl sulphide complex (2M solution in THF, 34 mL, 68.6 mmol). On completion of the reaction the mixture was carefully poured into MeOH and the resulting mixture heated at reflux for 30 minutes. The volatiles were removed in vacuo and the residue partitioned between dilute aqueous sodium hydrogencarbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on Isolute® flash silica gel (Separtis) to give 2-[(2-chloro-pyridin-4-ylmethylamino]-nicotinic acid methyl ester (0.76 g); 1H-NMR (300 MHz, d6-DMSO) 8.47 (1H, t), 8.30 (1H, d), 8.23 (1H, unresolved dd), 8.13 (1H, unresolved dd), 7.38 (1H, s), 7.30 (1H, d), 6.68 (1H, dd), 4.73 (2H, d), 3.85 (3H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:20][CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.O.Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:21]=[CH:22][N:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncc[nH]3)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3nccn3S(C)(=O)=O)cc2)cc1
Reaction time: 0.67 h

Procedure:
The product from Example 6 (71.4 mg, 0.224 mmol) and triethylamine (62 μL, 0.44 mmol) in CH2Cl2 (2 mL) at 0° C. were treated with methanesulfonyl chloride (21 μL, 0.27 mmol). The solution was stirred for 40 minutes, allowed to warm over 15 minutes, diluted with water (3 mL) and 1 N HCl (0.5 mL), and extracted with CH2Cl2 (3×4 mL). The extracts were combined, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (60% ethyl acetate in hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.96 (d, 2H), 7.85 (m, 3H), 7.57 (m, 3H), 7.41 (d, 2H), 7.22 (d, 1H), 3.02 (s, 3H), 1.33 (s, 9H); MS (m/z) 398.
Reaction SMILES: [F:1][CH:2]1[C:7]([Si](C)(C)C)=[C:6]([F:12])[CH:5]=[C:4]([S:13][CH3:14])[C:3]1([CH2:16][O:17][CH3:18])[OH:15].C(O)C(F)(F)F.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][CH:2]1[CH:7]=[C:6]([F:12])[CH:5]=[C:4]([S:13][CH3:14])[C:3]1([CH2:16][O:17][CH3:18])[OH:15]
Reactant: COCC1(O)C(SC)=CC(F)=C([Si](C)(C)C)C1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Product: COCC1(O)C(SC)=CC(F)=CC1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A reaction mixture containing the trimethylsilyl derivative (28, 0.51 g, 1.74 mmol) in 10 mL of freshly distilled THF was treated with trifluoroethanol (0.18 g, 1.82 mmol) and tetrabutylammonium fluoride (1 M solution in THF, 1.74 mL, 1.74 mmol) at −78° C. under argon (FIG. 2E). The reaction mixture was allowed to stir at −78° C. for 20 min and at room temperature for 30 minutes. The reaction was quenched by the addition of water, followed by extraction with ethyl ether (2×15 mL). The combined organic extracts were washed with water, dried (MgSO4), filtered, and the solvent removed under vacuo. Silica gel chromatography (5% EtOAc:hexanes) gave the pure product as a colorless oil (270 mg, 71%). 1H NMR (CDCl3) δ6.6-6.64 (m, 2 H, ArH), 5.11 (s, 2 H, CH2), 3.63 (s, 3 H, CH3), 2.42 (s, 3 H, CH3).