Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:14]2[CH2:26][CH2:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([Cl:27])[CH:22]=4)[N:17]([CH2:28][O:29][CH3:30])[C:16]=3[CH2:15]2)([CH3:13])[CH2:11][OH:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:33]I>C1COCC1>[C:1]1([S:7]([C:10]([CH:14]2[CH2:26][CH2:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([Cl:27])[CH:22]=4)[N:17]([CH2:28][O:29][CH3:30])[C:16]=3[CH2:15]2)([CH3:13])[CH2:11][O:12][CH3:33])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(CO)S(=O)(=O)c1ccccc1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(COC)S(=O)(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 71.7 %

Procedure:
130 mg (0.29 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propan-1-ol in 5 mL of THF at 0° C. were treated with 14 mg (0.32 mmol, 1.1 eq) of NaH (55% in oil) portionwise within 30 min. 30 min. 30 μL (0.43 mmol, 1.5 eq) of MeI were added and the reaction mixture was stirred an additional 2 hours, partitioned between EtOAc and a saturated aqueous solution of NH4Cl. The organic phase was washed with brine, dried over Na2SO4, and evaporated. Column chromatography with heptane/EtOAc 1:2 gave 96 mg (72%) of (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole as a white solid, MS: 479 (MNH4+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:25])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[N:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[OH:25][C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][N:4]=2)[N:9]([CH3:12])[C:8](=[O:13])[C:7]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2ncc(Br)cc21
Reactant: OB(O)c1ccccc1
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ncc(-c3ccccc3)cc21

Procedure:
The title compound was prepared similarly to the procedures described for Example 2 from tert-butyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamido)acetate (Example 1 (f)) and phenylboronic acid. MS (ESI, pos. ion) m/z: 354 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm: 8.86 (s, 1 H), 8.20 (s, 1 H), 7.84 (d, J=7.4 Hz, 2 H), 7.44-7.63 (m, 3 H), 4.16 (s, 2 H), 3.78 (s, 3 H).
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](=[O:34])(=[O:33])[NH2:32])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:32][C:1]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:9])(=[O:34])=[O:33])=[O:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
In a stream of nitrogen and at 0° C., 0.36 ml (2.87 mmol) of phenyl chlorocarbonate was added to an anhydrous tetrahydrofuran (10 ml) solution containing 1 g (2.60 mmol) of 3-benzyloxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 1 and 702 mg (5.75 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 1.00 g (yield: 77.0%) of the title compound.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][C@H:29]1[NH:34][CH2:33][CH2:32][N:31]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:30]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][C@H:13]([CH2:12][N:34]4[CH2:33][CH2:32][N:31]([C:35]5[CH:44]=[CH:43][C:42]6[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=6)[N:36]=5)[CH2:30][C@H:29]4[CH3:28])[O:27][C:17]3=2)[N:22]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)CCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4ccccc4n2)C[C@H]1C)O3
Temperature: 50 °C
Yield: 47.3 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (238 mg, 0.528 mmol) and (R)-2-(3-methyl-piperazin-1-yl)-quinoline (350 mg, 1.58 mmol) in anhydrous dimethylsulfoxide (6 mL) was heated at 50° C. overnight. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel (2/2/96 methanol/2 M ammonia in methanol/methylene chloride) afforded 110 mg (47%) of the title compound as an off-white solid: mp 78–82° C.; MS (ES) m/z441 [M+H]+; [α]D −33.0° (c 1.0, DMSO)
Reaction SMILES: [C:1]([C@:3]1([OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9])#[CH:2].Br[C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][N:18]3[C:22]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]3[C:16]=2[CH:37]=1>CS(C)=O.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>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH2:28][C:22]1[N:18]2[CH2:19][CH2:20][O:21][C:15]3[CH:14]=[CH:13][C:12]([C:2]#[C:1][C@:3]4([OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[C:4]4=[O:9])=[CH:37][C:16]=3[C:17]2=[N:24][C:23]=1[C:25]([NH2:27])=[O:26]
Reactant: NC(=O)c1nc2n(c1COc1ccccc1Cl)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(COc4ccccc4Cl)n2CCO3)C1=O
Yield: 23 %

Procedure:
Similar to as described in General Procedure E with the exceptions of using Pd(PPh3)4 in DMSO, 10-bromo-3-((2-chlorophenoxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as a colorless solid (12 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[C:11](\[C:17]#[N:18])/C(OCC)=O)/[CH2:6][CH2:5]2.[C-:19]#[N:20].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH2:11][C:17]#[N:18])([C:19]#[N:20])[CH2:6][CH2:5]2
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)ccc21
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC1(C#N)CCc2cc(Cl)ccc21
Temperature: 65 °C
Reaction time: 21 h
Yield: 43.7 %

Procedure:
To a solution of (E)-ethyl 2-(5-chloro-2,3-dihydro-1H-inden-1-ylidene)-2-cyanoacetate (Prep5, 100 g, 0.38 mol) in ethanol (800 ml) a solution of KCN (67.5 g, 1 mol) in water (230 ml) was added and the reaction mixture was warmed to 65° C. and stirred for 21 h. Then the solvent was removed under vacuum The residue was treated with ether and the organic phase washed with water. Solvent was evaporated and the crude obtained was purified by crystallization from ethanol to obtain the title compound (36 g, y=43.5%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 12 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (7.3 g, 30.5 mmol) in DMF (20 ml) was added potassium carbonate (5.47 g, 39.6 mmol) at room temperature followed by drop wise addition of 4-Trifluoromethylbenzyl bromide (6.04 g, 33.6 mmol). The reaction mixture was stirred for 12 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether 5:1) to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]nnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 8.10-8.20 (m, 1 H), 8.22-8.31 (m, 1 H), 8.49 (dt, J=8.1, 2.0, 1.7 Hz, 1 H), 8.75-8.92 (m, 2 H), 9.30 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[N:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([S:17]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)(=[O:18])=[O:19])=[CH:21][CH:22]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: Brc1nn2c(I)cnc2s1
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(-c2nn3c(I)cnc3s2)cc1)N1CCOCC1
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (200 mg, 0.44 mmol), 4-(4-morpholinylsulfonyl)phenylboronic acid (144 mg, 0.52 mmol), PdCl2(PPh3)2 (60 mg, 0.088 mmol) and 2M aq Na2CO3 (1.2 mL) in dioxane (8 mL) was heated at 90° C. for 18 h. The solvent was removed in vacuo and the residue was triturated from EtOAc and filtered. The filtrate was evaporated and the residue was recrystallyzed from MeOH to give the desired product (89 mg, 31%) as a brown solid.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([O:20][C:21](=O)[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)C=CC=CC=1>>[N:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:21]([N:12]2[C@@H:9]([CH2:8][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][C:11]2=[O:13])=[O:20])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccncc1)Oc1ccccc1
Reactant: O=C1CC(CSc2ccccc2)N1
Product: O=C1C[C@H](CSc2ccccc2)N1C(=O)NCc1ccncc1

Procedure:
Following the same procedure as in example 4, step D, but using 4-(phenylsulfanylmethyl)azetidin-2-one and (pyridin-4-ylmethyl)carbamic acid phenyl ester as reactants gave 2-oxo-4(R)-(phenylsulfanylmethyl)azetidine-1-carboxylic acid (pyridin-4-ylmethyl)amide as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9](OC)=[O:10])=[C:5]([N+:15]([O-])=O)[CH:4]=1)=[O:2]>CC(O)=O.O.[Fe]>[O:10]=[C:9]1[CH2:8][O:7][C:6]2[CH:13]=[CH:14][C:3]([CH:1]=[O:2])=[CH:4][C:5]=2[NH:15]1
Reactant: COC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc2c(c1)NC(=O)CO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 2-(4-formyl-2-nitrophenoxy)acetate (1) (1.381 g, 5.77 mmol) and iron (1.612 g, 28.9 mmol) in AcOH (23 mL). The reaction was stirred at 80° C. for 1 hr. The reaction was concentrated in vacuo and taken up in DCM/MeOH (1:1, 100 mL), filtered and the filtrate was concentrated in vacuo to give 4.3 g crude of a brown solid. The solid was taken up in water and filtered; the solid was washed with water and dried in vacuo to give a light brown solid (0.712 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.72 (s, 2 H) 7.14 (d, J=8.34 Hz, 1H) 7.38 (d, J=1.77 Hz, 1H) 7.54 (dd, J=8.21, 1.89 Hz, 1H) 9.84 (s, 1 H) 10.99 (s, 1H). ESI-MS: m/z 178.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[Cl:25])[C:8]2=[O:26])=[C:4]([F:29])[CH:3]=1.[C:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH3:46])=[CH:40][C:39]=1B(O)O)(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[CH2:12]([C:11]1[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([C:39]3[CH:40]=[C:41]([CH2:44][CH2:45][CH3:46])[CH:42]=[CH:43][C:38]=3[S:35](=[O:37])(=[O:36])[NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:3][C:4]=2[F:29])[C:8](=[O:26])[N:9]([C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=2[Cl:25])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 43 %

Procedure:
Using the method of Example 76, Step F, 4-(4-bromo-2-fluorobenzyl)-5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) was coupled with 2-(N-t-butylsulfamoyl)-5-n-propylphenylboronic acid (from Example 68, Step B). Flash chromatography of the crude product on silica gel (gradient elution with 6:1 to 2:1 hexane-EtOAc) gave a 43% yield of the title compound as a cream-colored solid, mp 84°-86° C.; homogeneous by TLC (4:1 hexane-EtOAc).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[C:30]([NH2:38])(B(O)O)[NH:31][CH:32]=[CH:33][CH:34]=1>>[CH3:28][C:29]1[C:30]([NH2:38])=[N:31][CH:32]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)[CH:34]=1
Reactant: CC1=CC=CNC1(N)B(O)O
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: Cc1cc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cnc1N
Yield: 80 %

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine and 3-methyl-2-aminopyridine boronic acid were reacted in General Procedure A Suzuki Coupling to produce 378 in 80% yield after RP-HPLC purification. MS (Q1) 504.2 (M)+, purity 100% by UV 254 nm, 1H NMR (DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](C)[CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22].BrC1C=CC([Cl:31])=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:31])=[CH:14][CH:13]=1)=[C:5]2[CH2:20][C:21]([OH:23])=[O:22]
Reactant: Clc1ccc(Br)cc1
Reactant: Cc1cccc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 18, step 1) and 4-bromochlorobenzene.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[Cl:8][C:7]1[C:2]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CCOC(=O)CO
Product: CCOC(=O)COc1nccnc1Cl

Procedure:
The title compound was synthesized from 2,3-dichloropyrazine and ethyl 2-hydroxyacetate in the same manner as in Example 19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Cl:11])=[N:6][CH:5]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH3:15])[C:7]([Cl:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cnc(Cl)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-chloro-5-hydroxynicotinic acid methyl ester (1.8 g, 9.6 mmol), methyl iodide (2 M solution in Et2O, 5.8 mL, 11.6 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in acetone (190 mL) was refluxed for 6 h. The reaction was then concentrated via rotavap and H2O was added (100 mL). The resulting white precipitate was filtered and rinsed with additional H2O to furnish the product 6-chloro-5-methoxynicotinic acid methyl ester as a white solid (1.33 g, 68%); mp=83-85° C.; 1H NMR (400 MHz, CDCl3) δ 8.60 (d, 1H), 7.77 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H): GC-MS: Exact mass calcd for C8H8ClNO3 [M]+, 201. Found 201.
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)CCl>[OH:17][C:16]1[C:15]2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4][C:2]([CH3:3])([CH3:1])[C:14]=2[CH:13]=[C:12]([CH3:18])[CH:11]=1
Reactant: Cc1cccc(O)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
2,5-Dimethyl-2,5-dichlorohexane (183 g, 1 mol) was stirred with m-cresol (129.6 g, 1.2 mol) and aluminum chloride (4 g) was added in one direction. The mixture was heated at 95° C., with stirring for 1.5 h, after which ethylene dichloride (100 mL) was added and then the heating was continued. After 1 h the mixture was cooled to 20° C. and poured onto an ice-water/hydrochloric acid mixture (150 mL, 10% HCl solution). The mixture was then extracted with toluene (500 mL). The organic layer was separated, washed with brine (3×50 mL) and dried (Na2SO4). The solvent was removed by distillation and the residue was crystallized from a hexane/benzene solvent mixture to give 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (171 g), mp 133°-134° C., GLC purity 99%+. 1H-NMR (CDCl3) δ 6.82 (1H, broad s), 6.35 (1 H, d, J=1.4 Hz), 4.72 (1H, s), 2.30 (3H, s), 1.71 (4H, m), 1.49 (6H, s), 1.34 (6H, s). 13C-NMR (CDCl3) δ 154.2 (1C, s), 147.8 (1C, s), 135.7 (1C, s), 128.0 (1C, s), 120.2 (1C, d), 114.6 (1C, d), 37.9 (1C, t), 35.2 (1C, t), 34.6 (1C, s), 33.7 (1C, s), 32.0 (2C, q), 28.5 (2C, q), 20.8 (1C, q). IR (KBr) 3,503 cm-1, MS (m/e) 218 (M+, 24.7), 203 (100.0), 161 (55.1), 147 (23.9), 57 (10.9).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][C@@H:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[CH3:30][C:27]([O:26][C:24](=[O:25])[C@H:12]([CH2:11][NH:10][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:28])[CH3:29]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 53.5 %

Procedure:
A mixture of 325 mg (2 mmoles) of 4,6-dichloro-5-methyl-pyrimidine (marketed by SPECS), 600 mg (2 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176) in 3 ml of dimethylformamide and 3 ml of diisopropylethylamine is heated at 120° C. overnight. The reaction medium is concentrated to dryness under vacuum and the residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. The residue is chromatographed on silicagel eluting with a gradient of heptane (100%) to a mixture of heptane-ethyl acetate (50-50). 450 mg (Yield=53%) of expected product is obtained in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([N:37]=CN(C)C)=[N:11][C:10](=[O:42])[C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([NH2:37])=[N:11][C:10](=[O:42])[C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)C(O)C1CNc2[nH]c(N)nc(=O)c2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 63 %

Procedure:
The product of step c) (3.1 g, 5.15 mmol) was dissolved in acetonitrile (ACN, 130 ml) and treated with 1N HCl (13 ml, 13 mmol). The mixture was stirred at room temperature until no starting material was present (˜18 h). The reaction mixture was neutralized by addition of a saturated solution of sodium bicarbonate. The solvent was then evaporated in vacuo (temp <40° C.) to give a light yellow solid. The solid was slurried in DCM (50 ml) and filtered. The filtrate was evaporated and the residue purified by flash silica-gel chromatography (gradient elution 0 to 20% methanol in DCM) to give the sub-titled product (1.75 g, 63%, ˜9:1 regioisomeric mixture). 1H NMR (CD3OD) δ 5.10-4.98 (m, 1H), 4.20-4.10 (m, 1H), 4.02-3.90 (m, 1H), 3.72 (d, J=12.3 Hz, 1H), 3.59 (d, J=9.6 Hz, 1H), 3.20 (dd, J=4.5 Hz, J=12.9 Hz, 1H), 2.16-1.96 (m, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 1.30 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H). MS: ESI (positive): 541 (M+H).