Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1COCC1.CO>[CH2:20]([O:22][C:23](=[O:47])[CH2:24][C@@H:25]([C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[N:26]([CH3:1])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)(=[O:28])=[O:29])[CH3:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(OC)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (3.9 g, 15 mmol) was added to a solution of sulfonamide 1-6 (4.5 g, 10 mmol) in THF (30 mL). To this solution was added a solution of diethyl azodicarboxylate (2.4 mL, 15 mmol) in THF/MeOH (10 mL/2.02 mL). A vigorous exotherm occurred and the reaction was stirred overnight at room temperature. The dark mixture was concentrated. The dark oily residue was purified by flash chromatography (40% EtOAc/hexanes) to give the desired product 1-7.
Reaction SMILES: CS([Cl:5])(=O)=O.Cl.Cl.Cl.[NH:9]1[CH:13]=[C:12]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][C:24]([C:26]4[CH:27]=N[CH:29]=[CH:30][CH:31]=4)=[CH:25][C:20]=3[CH2:19][N:18]([C:32](=[O:37])[C:33](F)(F)F)[CH:17]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:16]2)[N:11]=[CH:10]1.[CH3:45]CN(C(C)C)C(C)C>C(Cl)Cl>[ClH:5].[C:32]([N:18]1[CH2:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:45][CH:29]=[CH:30][CH:31]=3)[CH:23]=[CH:22][C:21]=2[N:15]([CH2:14][C:12]2[N:11]=[CH:10][NH:9][CH:13]=2)[CH2:16][C@H:17]1[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)(=[O:37])[CH3:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
Methylsulfonylchloride (0.031 ml, 0.39 mmol) was added dropwise to a solution of Compound B (0.070 g, 0.27 mmol) and DIEA (0.14 ml, 0.80 mmol) in methylene chloride (2 ml) at -78° C. The mixture was allowed to warm slowly to room temperature and was stirred at rt for 16h. The mixture was quenched with 10% NaHCO3 (10 ml) and the solution was extracted with methylene chloride (3×10 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography (19/1 methylene chloride/iPrOH) to afford Compound C (0.064 g, 85%) as a solid. MS (M+H)+ 343
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([NH:15][NH2:16])=[O:14])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.C(N(CC)CC)C.[CH:24]1([N:27]2[CH2:32][CH2:31][CH:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25]1>ClCCl.O>[CH:24]1([N:27]2[CH2:28][CH2:29][CH:30]([C:33]([NH:16][NH:15][C:13]([C:9]3[CH:10]=[C:11]([Cl:12])[C:2]([NH2:1])=[C:3]4[C:8]=3[O:7][CH2:6][CH2:5][CH2:4]4)=[O:14])=[O:34])[CH2:31][CH2:32]2)[CH2:26][CH2:25]1
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCCC2
Reactant: O=C(Cl)C1CCN(C2CC2)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c(Cl)cc(C(=O)NNC(=O)C2CCN(C3CC3)CC2)c2c1CCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a stirred solution of 5-amino-6-chloro chroman-8-carboxylic acid hydrazide (8.0 grams, 33.1 mmol, obtained in preparation 1) in dichloromethane (200 mL) cooled at 0° C., was added triethylamine (13.9 mL, 99.9 mmol) and a solution of 1-cyclopropylpiperidine-4-carbonyl chloride (11.0 grams) in dichloromethane (200 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours before diluting it with water (160 mL). The two layers were separated, the organic layer was dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain the title compound (10.5 grams).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH2:27][OH:28])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>ClCCl>[CH2:11]([C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:27]=[O:28])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1c(CO)ccc2c(OC)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1c(C=O)ccc2c(OC)cccc12
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
A solution of dimethylsulfoxide (0.54 mL) in dry dichloromethane (3 mL) was added with stirring to a chilled (<-60° C.) solution of oxalyl chloride (0.59 mL) in dry dichloromethane (15 mL) at such a rate that the reaction temperature did not exceed -60° C. After 15 minutes a solution of 1-butyl-5-methoxy-2-naphthalenemethanol (1.54 g) in dichloromethane (6 mL) was added while the reaction temperature was still maintained below -60° C. The reaction was allowed to proceed for 15 minutes then triethylamine (2.9 mL) was added to the chilled reaction and, after an additional 20 minutes the cooling bath was removed and the mixture was allowed to equilibrate to room temperature. After 2N hydrochloric acid (225 mL) was added, the layers were separated and the aqueous phase was extracted with dichloromethane (50 mL), then the combined organic extracts were dried (MgSO4) and evaporated to yield 1.6 g of 1-butyl-5 -methoxy-2-naphthalenecarboxaldehyde. Sublimation of a portion (50° C.; 0.1 mm) furnished the analytical sample, mp 61.5°-62.5° C. Anal. Calcd for C16H18O2 : C, 79.31; H, 7.49 Found: C, 79.02; H, 7.53
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:15]1[N:16]=[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:18]2[C:19](=[O:22])[C:20]=1[I:21])[CH2:13][CH3:14].C(N(CC)C(C)C)(C)C>C(O)C>[I:21][C:20]1[C:19](=[O:22])[N:18]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:17]2=[N:16][C:15]=1[CH:12]([NH:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2)[CH2:13][CH3:14]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CCC(N)c1nc2cccc(C)n2c(=O)c1I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-9H-purine (1.65 g, 0.008270 mol), 2-(1-aminopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.58 g, 0.00752 mol), and N,N-diisopropylethylamine (1.571 mL, 0.009022 mol) in ethanol (60 mL) was refluxed under nitrogen overnight. The mixture was concentrated and the resulting residue was purified on silica gel, eluting with 0 to 10% methanol in methylene chloride, to provide the desired product (2.86 g, 82.5%). LCMS calculated for C17H17IN7O (M+H)+: m/z=462.1. Found: 462.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.31 (2H, m), 8.19 (1H, s), 8.15 (1H, s), 7.69 (1H, dd, J=8.7 and 6.9 Hz), 7.44 (1H, d, J=8.7 Hz), 6.99 (1H, d, J=6.9 Hz), 5.69 (1H, m), 2.89 (3H, s), 1.91 (2H, m), 0.95 (3H, t, J=7.2 Hz) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:37][C:38]([O:40]CC)=[O:39])=[O:5])C.[OH-].[Na+].CCO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[C:38]([CH2:37][C:7]1[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=1)=[CH:11][CH:10]=2)([OH:40])=[O:39]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1c(C(=O)O)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)-2-ethoxycarbonylmethyl-5-(5-trifluoromethyl-2-pyridinyloxy)indole-3-carboxylic acid ethyl ester (80 mg, 0.13 mmol, see step (a) above), NaOH (aq, 1 M, 1.1 mL), EtOH (0.5 mL) and THF (0.5 mL) was stirred at 100° C. for 9 h, cooled, diluted with H2O and acidified to pH 5 with citric acid (aq, 1 M). The precipitate was collected, washed with H2O and Et2O to give the title compound, 30 mg (42%), mp 203° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:30]([NH:34][C:35]([NH:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([OH:10])=[O:9])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNC(=O)NC(C)(C)C)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.7 %

Procedure:
Ethyl 4-(aminomethyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 246; 200 mg; 0.424 mmol) was dissolved in DCM (4 ml). tert-Butyl isocyanate (130 mg; 1.28 mmol) was added and the mixture stirred at room temperature for 1 h. The solvent was removed in vacuo and the ester (215 mg), LCMS:561 was treated with LiOH/THF in a manner analogous to Example 31 to give the title compound (290 mg).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:20])(C)[C:13](N(C)OC)=O)=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[BrH:21].[C:22](=[O:25])([O-])[OH:23].[Na+]>O>[Br:21][CH2:3][CH2:2][CH2:1][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:20])([CH3:13])[C:22]([OH:23])=[O:25])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C([O-])O
Reactant: CON(C)C(=O)C(C)(C)c1ccc(C(=O)C2CC2)cc1
Reactant: Br
Agent: [Na+]
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCBr)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
Treat 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-N-methyl-N-methoxy-propionamide (0.15 g, 0.53 mmol) with 48% HBr (1 mL) for 2 hours at 80° C. Cool to room temperature, dilute with water (5 mL) and neutralize with aqueous sodium hydrogen carbonate until pH 7. Extract with methylene chloride (3×15 mL), dry (Na2SO4), filter and evaporate the solvent in vacuo. Purify by silica gel chromatography (3:1 hexane/ethyl acetate) to give the title compound (0.15 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH:30]1([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=4)[N:41]=3)[CH2:36][CH2:35]2)[CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:47][CH2:46][C:44]3[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:50][CH:49]=4)[N:41]=[C:40]([N:37]4[CH2:36][CH2:35][N:34]([CH2:33][CH:30]5[CH2:31][CH2:32]5)[CH2:39][CH2:38]4)[CH:45]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCN(CC3CC3)CC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(-c3ccc(C(F)(F)F)cc3)nc(N3CCN(CC4CC4)CC3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.5 %

Procedure:
A solution of acid 18 (463 mg, 1.5 mmol) in THF (30 mL) was added with DEPC (0.23 mL, 1.0 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27G (560 mg, 1.04 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (9:1 EtOAc:methanol) to afford a white solid (220 mg) after crystallization from diethyl ether. Yield=21.5%, 1HNMR (DMSO, 200 MHz) δ 0.40 (m, 2H), 0.65 (bm, 2H), 0.94 (m, 1H), 1.12 (m, 2H), 1.28 (t, 3H), 1.40 (bm, 2H), 3.04 (bm, 4H), 3.39 (bm, 4H), 3.43 (bm, 2H), 3.44 (m, 4H); 4.40 (bm, 4H), 6.87 (s, 1H), 7.30 (m, 2H), 7.60 (d, 1H, J=3.2), 7.82 (d, 2H, J=8.2), 8.25 (bm, 3H). [M+1] 682.98 (C31H35ClF3N5O3S2 requires 682.22).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[CH3:7][N:6]1[C:2]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: Cn1ncc([N+](=O)[O-])c1O[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 93 %

Procedure:
Following the procedure for Example 230, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate gave (R)-tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate as a pale yellow oil (0.34 g, 93%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.15-4.85 (m, 1H), 3.84-3.72 (m, 2H), 3.69 (s, 3H), 3.41 (d, J=14.2 Hz, 1H), 3.30-3.13 (m, 1H), 2.11-2.02 (m, 1H), 1.94-1.82 (m, 2H), 1.63-1.52 (m, 1H), 1.42 (s, 9H)
Reaction SMILES: [NH2:1][C:2]([CH2:6][CH3:7])=[CH:3][C:4]#[N:5].[C:8]([CH2:12][C:13]([O:15]C)=O)(=O)[CH2:9][CH3:10].[OH-:17].[Na+]>CO>[NH2:5][C:4]1[CH:3]=[C:2]([CH2:6][CH3:7])[N:1]=[C:8]([CH2:9][CH3:10])[C:12]=1[C:13]([OH:15])=[O:17]
Reactant: [OH-]
Reactant: CCC(N)=CC#N
Reactant: CCC(=O)CC(=O)OC
Agent: [Na+]
Solvent: CO
Product: CCc1cc(N)c(C(=O)O)c(CC)n1
Temperature: 25 °C

Procedure:
Methyl 4-amino-2,6-diethylpyridine-3-carboxylate (3.94 g), itself obtained using an analogous procedure to that described in Tet. Lett., 1990, 3485 but starting from 3-amino-2-pentenenitrile (obtained as described in J. Het. Chem., 1989, 26, 1575) and methyl propionylacetate, is added to a mixture of 2M sodium hydroxide solution (9.5 ml) and methanol (40 ml) and the mixture is heated at reflux for 16 hours. The solution is cooled to ambient temperature and volatile material is removed by evaporation. The residue is partitioned between ethyl acetate and a mixture of 2M hydrochloric acid (9.5 ml) and water (20 ml). The aqueous phase is separated, water is removed by evaporation and the residue is extracted with ethyl acetate/methanol (1:1 v/v). The combined organic extracts are filtered and solvent is removed from the filtrate by evaporation to give 4-amino-2,6-diethylpyridine-3-carboxylic acid (3.46 g) as a yellow-brown foam; NMR (d6 -DMSO): 1.18(m,6H), 2.64(q,2H), 3.12 (q,2H), 6.49(s,1H), 8.28(broad s,2H),; mass spectrum (chemical ionisation, ammonia): 195(M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42](O)[CH2:41]2>C(#N)C>[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42]([O:13][C:12](=[O:14])[CH:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([F:2])[CH:4]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:41]2
Reactant: Cc1ccc(NC(C(=O)O)c2ccccc2)cc1F
Reactant: O[C@H]1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
(3-Fluoro-4-methyl-phenylamino)-phenyl-acetic acid hydrochloride (I48) (250 mg, 0.84 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (321 mg, 0.84 mmol), and HOBT (129 mg, 0.84 mmol) are dissolved in acetonitrile (6 mL). DIPEA (0.29 mL, 1.69 mmol) is added, followed by (R)-quinuclidin-3-ol (215 mg, 1.69 mmol) and the resulting yellow solution is stirred at RT overnight (Conversion complete by UPLC/MS-UV). MeCN is evaporated, the residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated. The crude compound is purified by filtration through a pad of silica using DCM/MeOH=9/1 as the eluent to obtain the title compound as a yellow oil (311 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1)[CH:14]=[CH2:13]
Reactant: CCOC(=O)c1cc(Cl)ccn1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1ccnc(C(=O)OCC)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of ethyl 4-chloropyridin-2-carboxylate (0.37 g) and allyltributyltin (IV) (0.86 mL) in toluene (5.0 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.12 g). The reaction mixture was stirred under nitrogen atmosphere at 120° C. for 12 hr. The solvent of the reaction mixture was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=3/2) to give the title compound (0.28 g, 73%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10](Br)[C:5]2=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccncc1B(O)O
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)nn2c(Br)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
A microwave vial was charged with a mixture of 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 3.21 mmol), 4-methylpyridin-3-ylboronic acid (0.440 g, 3.21 mmol), tetrakis(triphenylphosphine)palladium(0) (0.371 g, 0.321 mmol), dioxane (16 mL), and K3PO4 (4.82 mL, 9.64 mmol) (2.0 M solution in water) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 4 h in a microwave heater. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (20-80% EtOAc/CH2Cl2, 1.5 L, then 20%-65% B/CH2Cl2 (0.9 L); B: 10% MeOH/CH2Cl2) to give 320 mg (15.4%) product. 1H NMR (400 MHz, CD3OD) δ ppm 8.91 (1H, s), 8.82 (1H, d, J=5.79 Hz), 8.04 (1H, d, J=5.79 Hz), 7.88 (1H, s), 7.57 (1H, s), 2.54 (3H, s). LC (Conditions B & C): >95% purity; LC/MS: Rt=1.47 min. LC/MS (Condition A): 322.96/324.96.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].Cl.[CH2:31]([NH2:33])[CH3:32].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH2:31][CH3:32])=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with ethylamine hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=441.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[N:48]=[CH:47][N:46]=[C:45]2[C:41]=1[N:42]=[CH:43][N:44]2[CH2:49][C:50](O)=[O:51])=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:44]1[CH:43]=[N:42][C:41]2[C:45]1=[N:46][CH:47]=[N:48][C:40]=2[NH:39][C:37]([O:36][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:38])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Yield: 79.9 %

Procedure:
The title compound (2.91 g, 80%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 m mol) and [6-N-(benzhydryloxycarbonyl)-adenin-9-yl]-acetic acid (2.02 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.93 (s, 1H), 9.00 (s, 0.6H), 8.60 (s, 0.4H), 8.59 (s, 0.4H), 8.54 (s, 0.6H), 8.33 (d, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 7.69 (m, 2H), 7.52-7.29 (m, 10H), 6.83 (s, 1H), 5.47 (s, 1.2H), 5.37 (s, 0.8H), 4.47 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.03 (q, 1.2H), 3.71 (t, 1.2H), 3.61 (q, 1.2H) 3.49 (t, 0.8H) 3.42 (q, 0.8H), 1.24 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cc(-c2cc(-c3nnc(CN4CCOCC4)o3)c3cn[nH]c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
N-(2-Chloro-5-{1-[(4-methylphenyl)sulfonyl]-4-[5-(4-morpholinylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (52 mg, 0.081 mmol) was placed in isopropanol (3 ml) and 2M sodium hydroxide (1 ml, 2.0 mmol) added. The mixture was stirred at room temperature overnight and blown to dryness under a stream of nitrogen. The mixture was dissolved in water (10 ml) and washed with dichloromethane (10 ml). The organic layer was acidified by the addition of 2M hydrochloric acid and the solvent removed. The residue was purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound (8 mg).