Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH:20]=[CH2:21])[CH:13]=2)[CH:6]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[CH:13]=2)[CH:6]=1)[CH3:2]
Reactant: C=CCc1cc(Oc2cccc(C(=O)OCC)c2)ccc1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(Oc2cccc(C(=O)OCC)c2)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
To a solution of 3-(3-allyl-4-hydroxyphenoxy)benzoic acid ethyl ester (Gapinski, D. M.; Mallet, B. E.; Froelich, L. L.; Jackson, W. T., J. Med. Chem., 33, 2798-2813 (1990) incorporated herein by reference; 2.45 g) in methanol (15 mL) was added 10% palladium-on-carbon (300 mg). Hydrogen was bubbled through the resulting suspension for 5 minutes. The mixture was placed under 1 arm of hydrogen with stirring for 48 hours at room temperature. The mixture was de-gassed with nitrogen, filtered, and concentrated in vacuo to give 2.38 g (96%) of the title product as a colorless oil: 1H-NMR (CDCl3) 7.74 (d, J=8 Hz, 1H), 7.64 (d, J=2 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.15 (dd, J=9, 2 Hz, 1H), 6.86 (dd, J=2 Hz, 1H), 6.78 (m, 2H), 5.14 (bs, 1H, --OH), 4.38 (q, J=7 Hz, 2H), 2.59 (t, J=7 Hz, 2H), 1.65 (hextet, J=8 Hz, 2H), 1.39 (t, J=7 Hz, 3H), 0.98 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH3:25])[C:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:14]=[CH:13]2)=[O:11])[CH2:5][CH2:4]1)#[N:2].C([Sn](CCCC)=O)CCC.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38]>C1(C)C=CC=CC=1>[N:2]1[NH:36][N:37]=[N:38][C:1]=1[N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH3:25])[C:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[N:14]=[CH:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCN(C#N)CC3)cn2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCN(c4nn[nH]n4)CC3)cn2)cc1
Yield: 58.8 %

Procedure:
To a suspension of N-(1-cyanopiperidin-4-yl)-4-(4-methoxyphenyl)-N-methyl-1H-imidazole-1-carboxamide (151 mg, 0.445 mmol) in toluene (10 mL) was added dibutylstannanone (13.84 mg, 0.056 mmol) followed by azidotrimethylsilane (0.207 mL, 1.557 mmol). The reaction mixture was heated at reflux for 5 h, whereupon it was filtered still hot and the resulting pink solid was washed sequentially with toluene, dichloromethane and then finally ether. The solid was recrystallised from methanol to give the product as a light pink solid, (100 mg, 56%).
Reaction SMILES: C([O-])([O-])=O.[K+:5].[K+].[CH3:7][N:8]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=2[CH:10]=[CH:9]1>O.CO>[K+:5].[CH3:7][N:8]1[C:15]2[CH:14]=[C:13]([C:16]([O-:18])=[O:17])[NH:12][C:11]=2[CH:10]=[CH:9]1
Reactant: Cn1ccc2[nH]c(C(=O)O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cn1ccc2[nH]c(C(=O)[O-])cc21
Reaction time: 0.33 h
Yield: 182.2 %

Procedure:
To a suspension of K2CO3 (0.110 g, 0.798 mmol) in H2O (0.4 mL) and MeOH (2 mL) was added a solution of 4-methyl-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid 12 (262 mg, 1.60 mmol) in MeOH (2 mL). The solution was stirred for 20 min and was then concentrated in vacuo to give potassium-4-methyl-1,4-dihydro-pyrrolo[3,2-b]pyrrole-2-carboxylate 12a as a grey solid (294 mg, 91%). 1H NMR (400 MHz, (CD3)2SO) δ (ppm) 9.80 (s, 1H) 6.58 (d, J=2.8 Hz, 1H) 6.10 (s, 1H) 5.70 (dd, J=2.8, 0.8 Hz, 1H) 3.55-3.57 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)([CH3:6])[C:3](=[O:5])[CH3:4].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)[CH3:6]
Reactant: CC(=O)C(C)(C)c1nc(C)no1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: Cc1noc(C(C)(C)C(=O)C=CN(C)C)n1

Procedure:
3-Methyl-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (101 mg, 0.6 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (140 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(C[C@@H](N)CC([N:38]2[CH2:50][C:42]3=[N:43][N:44]=[C:45]([C:46]([F:49])([F:48])[F:47])[N:41]3[CH2:40][CH2:39]2)=O)=C(F)C=C(F)C=1F.O.OP(O)(O)=O.CCN(C(C)C)C(C)C.Cl.FC(F)(F)C1N2CCNCC2=NN=1.ClC1C=CC(B(O)O)=CC=1.C(OC(C)C)(C)C>O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11](=[O:13])[N:38]1[CH2:39][CH2:40][N:41]2[C:45]([C:46]([F:49])([F:47])[F:48])=[N:44][N:43]=[C:42]2[CH2:50]1)[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: FC(F)(F)c1nnc2n1CCNC2
Agent: O=P(O)(O)O
Solvent: CC(C)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid of formula (II) was charged with 40 ml of toluene into a 500 ml 4 necked round bottom flask attached with dean stark apparatus followed by 5 ml of Hunig's base at room temperature. Then 5 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine HCl was charged and stirred for 5 minutes. 2.34 g of 4-chloro phenyl boronic acid was charged to the reaction mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was cooled to room temperature and 50 ml of water was added to it. The organic layer was separated and washed twice with 25 ml of 1N HCl. The organic layer was separated and washed with 25 ml of water followed by 6% NaHCO3 and finally by 25 ml of water. The organic layer was then separated, treated with sodium sulfate and then with charcoal and filtered. The solvent was distilled out under vacuum. The solid obtained was stirred with 25 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether and then dried under vacuum at 50° C. for 12-15 hours.
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]3[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([OH:26])[O:20][C@@H:19]3[CH2:27][OH:28])[O:11][C@@H:10]2[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33].[CH2:35]([OH:57])[C@H:36]1[O:41][C@H:40]([O:42][C@H:43]2[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[O:45][C@@H:44]2[CH2:52][OH:53])[C@H:39]([OH:54])[C@@H:38]([OH:55])[C@@H:37]1[OH:56]>C([O-])(=O)C>[CH2:35]([OH:57])[C@H:36]1[O:41][C@H:40]([O:34][CH2:1][C@H:2]2[O:7][C@H:6]([O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[CH:21]([OH:26])[O:20][C@@H:19]4[CH2:27][OH:28])[O:11][C@@H:10]3[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]2[OH:33])[C@H:39]([OH:54])[C@@H:38]([OH:55])[C@@H:37]1[OH:56].[CH2:35]([OH:57])[C@H:36]1[O:41][C@H:40]([O:42][C@H:43]2[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[O:45][C@@H:44]2[CH2:52][OH:53])[C@H:39]([OH:54])[C@@H:38]([OH:55])[C@@H:37]1[OH:56]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Product: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)C(O)O[C@@H]4CO)O[C@@H]3CO)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 100 °C

Procedure:
The activities of these enzymes were assayed as follows: The α-isomaltosylglucosaccharide-forming enzyme of the present invention was assayed for enzymatic activity by dissolving maltotriose in 100 mM acetate buffer (pH 6.0) to give a concentration of 2% (w/v) for a substrate solution, adding a 0.5 ml of an enzyme solution to a 0.5 ml of the substrate solution, enzymatically reacting the mixture solution at 35° C. for 60 min, suspending the reaction mixture by heating at 100° C. for 10 min, and quantifying maltose, among the isomaltosyl maltose and maltose formed in the reaction mixture, by high-performance liquid chromatography (abbreviated as “HPLC” hereinafter). HPLC was carried out using “YMC PACK ODS-AQ303 column” commercialized by YMC Co., Ltd., Tokyo, Japan, at a column temperature of 40° C. and a flow rate of 0.5 ml/min of water; and using “RI-8012”, a differential refractometer commercialized by Tosoh Corporation, Tokyo, Japan. One unit activity of the α-isomaltosylglucosaccharide-forming enzyme is defined as the enzyme amount that forms one micromole of maltose per minute under the above enzymatic reaction conditions.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:7][N:6]2[CH:8]=1
Reactant: c1cn[nH]c1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(Br)ccc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(-n3cccn3)ccc2n1
Yield: 16 %

Procedure:
As described for Example 60, 6-bromo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (70.8 mg, 0.2 mmol) instead of 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine was converted, using pyrazole instead of benzamide, to the title compound (11 mg, 16%) which was obtained as a light yellow gum. MS: m/e=342.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]([O:11]CC)=[O:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Li+].[Cl-].OS([O-])(=O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/C(=O)O
Yield: 82 %

Procedure:
4-1 (340 mg, 1.7 mmol) was stirred for 1 h at rt with a solution comprised of 4 mL THF, and 4 mL of a solution containing 1 M NaOH and 1 M LiCl. The resulting mixture was acidified to pH 3-4 with 1 M KHSO4 and extracted twice with 30 mL of EtOAc. The extract was washed with 30 mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting material was subjected to silica gel flash chromatography using a gradient of 5–10% methanol in DCM to yield 240 mg (82% yield) of 4-2.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH:22]=[CH:21]1>>[O:18]=[C:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH:22]=[CH:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: O=C1CCc2cccc(N3CCNCC3)c2N1
Agent: Cl
Product: O=C1CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c2N1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 448.3 (Exact Mass: 447.23).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([N:14]1[C:18]([S:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:17][N:16]=[N:15]1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1>>[CH2:1]([O:8][C:9]([NH:11][CH:12]([N:14]1[C:18]([SH:19])=[N:17][N:16]=[N:15]1)[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)OCc1ccccc1)n1nnnc1SC(c1ccccc1)c1ccccc1
Solvent: Oc1ccccc1
Product: CC(NC(=O)OCc1ccccc1)n1nnnc1S
Yield: 62 %

Procedure:
TEA (63 ml.) was added to 9.4 g. (0.0211 M.) of 1-benzyloxycarbonylaminoethyl-5-diphenylmethylthiotetrazole and 9.4 g. (0.1 M.) phenol and left standing at room temperature for 31/2 hours. The TFA was then evaporated off at 40° C. (15 mm.). The resulting oily residue was added to 63 ml. of a 5% NaHCO3 solution and 30 ml. of ether and titrated with concentrated NaOH to pH 8.2. The phases were separated and the aqueous water phase was titrated to pH 2 with concentrated hydrochloric acid, extracted twice with 60 ml. ether and the ether was evaporated to give an oil. The oil was azeotroped with ethyl acetate and crystallized by scratching with a glass rod to give 1-benzyloxycarbonylaminoethyl-5-mercaptotetrazole which was washed with 100 ml. "Skellysolve-B". 3.67 g. (62% yield) was collected by filtration.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([C:31]#[N:32])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)=[O:12].C(N(C(C)C)CC)(C)C.[F:42][C:43]([F:53])([F:52])[C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Br)=[CH:46][CH:45]=1>ClCCl>[CH:28]([C:27]1[C:21]2[O:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:2]4[CH2:3][CH2:4][C:5]5([CH2:10][CH2:9][N:8]([CH2:48][C:47]6[CH:46]=[CH:45][C:44]([C:43]([F:42])([F:52])[F:53])=[CH:51][CH:50]=6)[CH2:7][CH2:6]5)[CH2:1]4)=[O:12])=[CH:18][CH:17]=3)=[N:23][C:22]=2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(Cc6ccc(C(F)(F)F)cc6)CC5)C4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 2-[4-(2,8-diazaspiro[4.5]dec-2-ylcarbonyl)phenyl]-7-isopropyl-1,3-benzoxazole-5-carbonitrile (25 mg, 0.046 mmol, EXAMPLE 121, Step B) in dichloromethane (2 ml) were added diisopropylethylamine (20 μl, 0.115 mmol) and 4-(trifluoromethyl)benzyl bromide (17 mg, 0.071 mmol). The mixture was stirred at room temperature overnight, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (21.4 mg, 0.036 mmol, 79% yield). Mass spectrum (ESI) 587.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:24]=1[N:38]1[CH2:50][CH2:49][N:41]2[C:42]3[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=3[CH:48]=[C:40]2[C:39]1=[O:51])(=[O:20])[CH3:19].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 21.2 %

Procedure:
A mixture of 142a (510 mg, 1.7 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (882 mg, 1.9 mmol), CH3COONa (309 mg, 3.8 mmol), PdCl2(dppf) (153 mg, 0.19 mmol), and K3PO4 (1 g, 3.8 mmol) suspended in CH3CN (30 mL) and H2O (2 mL) was heated at 110° C. for 15 h under argon atmosphere. It was then evaporated and the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 1:4 water/CH3CN to give 142b as a brown solid (200 mg, 21%). LCMS: [M+H]+ 555.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:27])([F:15])[F:28])=[CH:22][CH:21]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)Cc2ccc(C(F)(F)F)cc2)nn2cccnc12

Procedure:
The product from Example 105B and 2-(4-(trifluoromethyl)phenyl)acetic acid were processed using the method analogous to that described in Example 137 to afford the title compound. 1H NMR (400 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.87 (dd, J=6.9, 1.0 Hz, 1H), 8.49 (dd, J=4.0, 1.8 Hz, 1H), 7.67-7.75 (m, 2H), 7.51-7.64 (m, 2H), 7.01 (dd, J=7.0, 4.0 Hz, 1H), 3.75-3.80 (bs, 2H), 1.39 (s, 9H); MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][S:8](=[O:31])(=[O:30])[N:9]([C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[N:20]=1)[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(C)(C)C.Cl>>[CH:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:16]([N:9]([CH2:10][C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[S:8]([CH2:7][C:6]([OH:32])=[O:5])(=[O:30])=[O:31])[S:17][CH:18]=2)=[CH:26][CH:25]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1ccc(-c2csc(N(Cc3cccs3)S(=O)(=O)CC(=O)OC(C)(C)C)n2)cc1
Agent: Cl
Product: CC(C)c1ccc(-c2csc(N(Cc3cccs3)S(=O)(=O)CC(=O)O)n2)cc1

Procedure:
The above ester was treated with 4M HCl as outlined in general procedure G1 to provide {[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-thiophen-2-ylmethyl-sulfamoyl}-acetic acid. LCMS m/z: 438 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(#N)C>[NH:22]([C:2]1[N:7]=[N:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1)[NH2:23]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)nn2)CC1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(NN)nn2)CC1
Temperature: 80 °C
Yield: 58.7 %

Procedure:
A stirred mixture of tert-butyl 4-(6-chloropyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (870 mg, 2.94 mmol) and hydrazine hydrate (4.29 mL, 88.25 mmol) in acetonitrile (15 mL) was heated at 80° C. for 4 hours. The mixture was partially evaporated (removing MeCN) and diluted with water (10 mL). The reaction mixture was extracted with DCM (3×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product as a gum, which crystallised on trituration with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford tert-butyl 4-(6-hydrazinylpyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (503 mg, 58.7%) as a cream crystalline solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[C:3]=1[F:17].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[C:3]=2[F:17])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1NCCn2c1cc1cc(F)c(F)c(Br)c12
Product: O=C1NCCn2c1cc1cc(F)c(F)c(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, white solid (61 mg, 73%), MS (ISP) m/z=335.2 [(M+H)+], mp 305° C., was prepared in accordance with the general method of example 1 from 6-bromo-7,8-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (75.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ncccc3F)sc2N)c1N1CC[C@H](N)[C@@H](F)CC1
Yield: 72 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid gave 297 as a pale brown solid (424 mg, 72% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.39 (dt, J=4.6, 1.4 Hz, 1H), 7.86 (s, 1H), 7.52 (ddd, J=10.8, 8.3, 1.4 Hz, 1H), 7.32-7.26 (m, 1H), 6.32 (s, 2H), 4.51 (dtd, J=47.9, 8.5, 3.6 Hz, 1H), 3.73 (s, 3H), 3.40-3.17 (m, 5H), 2.34-2.19 (m, 1H), 2.16-1.96 (m, 2H), 1.79-1.66 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 449 (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C[O:23][CH:24]=[C:25]([C:30](OC)=O)[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[O:23]=[C:24]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:10][C:11]=3[C:2]2=[N:1][CH:30]=[C:25]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
A mixture of 4-amino-6-(3-cyclopentylpropionamido)-quinazoline (7.05 g) and dimethyl methoxymethylenepropanedioate (6.48 g) in N,N-dimethylformamide (28 ml) was stirred at 100° C. for 1 hour and 10 minutes. After cooling to ambient temperature, water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. The crude crystals were dissolved in a mixture of chloroform and methanol, treated with activated charcoal, and evaporated under reduced pressure until crystallization began. After cooling, the resulting solid was collected, washed with methanol and with dichloromethane, and dried. There was obtained crystalline methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (2.16 g). The filtrate was evaporated under reduced pressure to give a residue which was chromatographed on silica gel with 1% methanoldichloromethane. The first fractions contained methyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.9 g). The second fractions contained dimethyl[[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]methylene]propanedioate (5.16 g).