Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].C(N(CC)CC)C>ClCCl>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1)[CH3:31]
Reactant: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26) (37 mg, 0.099 mmol) was combined with 1-hydrobenzotriazole hydrate (23.0 mg, 0.149 mmol), N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (29.0 mg, 0.149 mmol), and beta-alanine ethyl ester hydrochloride (18.0 mg, 0.119 mmol). Anhydrous dichloromethane (5 mL) was added followed by triethylamine (0.027 mL, 0.198 mmol). The solution was stirred at room temperature for 3 d before partitioning between ethyl acetate and aq. sat. ammonium chloride. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (37.9 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.2 Hz, 2H) 7.59 (t, J=3.9 Hz, 2H) 7.46-7.52 (m, 3H) 7.37-7.45 (m, 1H) 7.11-7.19 (m, 1H) 6.75 (t, J=5.8 Hz, 1H) 5.32 (dd, J=9.7, 6.7 Hz, 1H) 4.75 (d, J=6.6 Hz, 1H) 4.10-4.21 (m, 2H) 3.70 (q, J=6.0 Hz, 2H) 2.55-2.74 (m, 3H) 2.29 (s, 3H) 1.96 (ddd, J=11.1, 8.2, 2.9 Hz, 1H) 1.75-1.84 (m, 1H) 1.64-1.73 (m, 2H) 1.26 (m, 3H) 1.16 (s, 3H) 1.09 (s, 3H); MS (M+1): 474.7.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:15])[NH:6]1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:15])[NH:6]1
Reactant: [N-]=[N+]=NCC1Cc2ccccc2C(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCC1Cc2ccccc2C(=O)N1
Reaction time: 8 h

Procedure:
Dissolve 3-(azidomethyl)-3,4-dihydro-2H-isoquinolin-1-one (1.8 g, 8.9 mmol) in EtOAc (15 mL). Under a nitrogen atmosphere add 10% Pd/C (0.2 g) then stir overnight under a hydrogen atmosphere. Filter reaction mixture through Celite® and wash the Celite® with EtOAc. MS (m/z): 177 (M+1).
Reaction SMILES: [ClH:1].[C:2]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=[CH:3]2>>[Cl:1][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3]1
Reactant: Cl
Reactant: C1=CC2(CCCC2)c2ccccc21
Product: ClC1CC2(CCCC2)c2ccccc21
Yield: 95 %

Procedure:
Anhydrous hydrogenchloride gas is bubbled through spiro(cyclopentane-1,1'-indene) (117.5 g; 0.69 moles) until 25 g have absorbed. The temperature is held under +10° C. by cooling on an ice bath. The liquid obtained is distilled and at first a small amount of unreacted spiro-cyclopentaneindene passes over, followed by about 135 g (Yield 95%) 3'-chlorospiro(cyclopentane-1,1'-indan) bp 97° C./0.7 mm Hg. nD20 =1.5625.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:37][O:38][CH2:39][CH2:40]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH2:40][CH2:39][O:38][CH3:37])[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCC(n2nc(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)c3c(N)ncnc32)C1
Temperature: 65 °C
Reaction time: 18 h
Yield: 29.3 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.250 g, 0.518 mmol) in dimethylformamide (5 mL) was treated with 2-bromoethyl methyl ether (0.079 g, 0.569 mmol) and potassium carbonate (0.143 g, 1.04 mmol). The reaction mixture was stirred at 65° C. for 18 h under a nitrogen atmosphere. Water (25 mL) was added to the reaction mixture. The precipitate formed was filtered and dried on the lyophilizer. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (15 min), 20% methanol in dichloromethane (20 min) and 50% methanol in dichloromethane (5 min) as the eluent. The column afforded 0.082 g (29%) of pure N2-(4-{4-amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.447 (s, 1H), 8.265 (s, 1H), 8.1278-8.1075 (d, 1H, J=8.12 Hz), 7.7192-7.6993 (d, 1H, J=7.96 Hz), 7.5996-7.5799 (d, 1H, J=7.88 Hz), 7.349-7.295 (m, 4H), 7.172-7.133 (m, 1H), 5.42 (m, 1H), 4.042 (s, 3H), 3.96 (s, 3H), 3.479 (m, 2H), 3.266-3.258 (m, 3H), 2.95-2.60 (m, 4H), 2.332 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.34 min (100%), MH+ 541.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.C([Si](C)(C)[N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](B(O)O)=[CH:25]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:25]1
Reactant: CC(C)(C)[Si](C)(C)n1cc(B(O)O)c2ccccc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4ccccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Step C of Method C, starting from (4-chloro-pyrimidin-2-yl)(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and [1-(tert-butyl-dimethyl-silanyl)-1H-indol-3-yl]-boronic acid using bis(triphenylphosphine)palladium(II) dichloride as a catalyst. The TBDMS protecting group was cleaved in situ by addition of catalytic amounts of TBAF. Yield: 2.2 g (86%).
Reaction SMILES: [C:1]([C:3]1([OH:18])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[CH:2].[CH2:19]([CH:22]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)[CH2:20][CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:18][C:3]2([C:1]#[CH:2])[CH2:8][CH2:7][CH:6]([CH:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]3)[CH2:5][CH2:4]2)=[O:29])[CH2:24][CH2:23]1)[CH2:20][CH3:21]
Reactant: CCCC1CCC(C(=O)O)CC1
Reactant: C#CC1(O)CCC(C2CCC(CCC)CC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC1(OC(=O)C2CCC(CCC)CC2)CCC(C2CCC(CCC)CC2)CC1
Reaction time: 8 h

Procedure:
4.00 g of 4-(dimethylamino)pyridine are added to a solution of 16.00 g of 4-ethynyl-4′-propylbicyclohexyl-4-ol and 11.51 g of 4-propylcyclohexanecarboxylic acid in 120 ml of dichloromethane. 9.66 g of N,N-dicyclohexylcarbodiimide in 30 ml of methylene chloride are subsequently added dropwise at RT, and the mixture is stirred overnight. Conventional work-up gives 4-ethynyl-4′-propylbicyclohexyl-4-yl 4-propylcyclohexane-carboxylate (C 59 N 120 I, Δε−1.57, Δn 0.04).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:25][CH3:26])=[CH:12][C:11]=1[CH3:27])(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)C>Cl>[CH3:27][C:11]1[CH:12]=[C:13]([O:25][CH3:26])[C:14]([NH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][C:10]=1[OH:9]
Reactant: COc1cc(C)c(OC(=O)c2ccccc2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C)c(O)cc1NC(=O)c1ccccc1
Temperature: 100 °C
Yield: 55.4 %

Procedure:
3 g (8.3 mmol) of 2-methyl-4-methoxy-5-benzoylaminophenyl benzoate was added into the mixture of 50 ml of sodium hydroxide and 50 ml of ethanol and the solution was heated at 100° C. under reflux for 2.5 hours. 40 ml of IN hydrochloric acid was added to the reaction mixture and precipitates were filtered, washed with water and recrystallized from ethanol to give 1.2 g (4.6 mmol) of 2-methyl-4-methoxy-5-benzoylaminophenol in the form of pale yellow plate-like crystals. The yield was 78%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[C@H:31]([CH2:32][OH:33])[CH2:30][CH2:29][C:28]5=[O:34])=[CH:23][C:22]=4[F:35])=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)(O[CH3:40])(=O)=O>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[C@H:31]([CH2:32][O:33][CH3:40])[CH2:30][CH2:29][C:28]5=[O:34])=[CH:23][C:22]=4[F:35])=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(N2C(=O)CC[C@H]2CO)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COC[C@@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(F)c1

Procedure:
Using (S)-1-{4-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (130 mg) described in Example 294 and methyl tosylate (41 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (8 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH:5]=[C:4]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=[O:20])[C:3]1=[O:24])=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:20][CH2:19][C:18]1[CH:17]=[C:16]([C:4]2[C:3](=[O:24])[N:2]([CH3:1])[C:7]3[NH:8][C:9]4[C:14]([C:6]=3[CH:5]=2)=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=4)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc2[nH]c3c(cc(-c4cccc(C=O)c4)c(=O)n3C)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc2[nH]c3c(cc(-c4cccc(CO)c4)c(=O)n3C)c2c1
Reaction time: 18 h
Yield: 71 %

Procedure:
280 mg of the compound obtained in Stage A are placed in 10 ml of CH2Cl2 and the minimum amount of AcOH to dissolve the compound, 375 mg of NaBH(OAc)3 are added and then the mixture is left stirring at AT for 18 hours. The reaction medium is evaporated and the residue is taken up in AcOEt and then filtration is carried out to produce 200 mg of the expected compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[N:30]1([C:34]([C:36]2[S:40][C:39](Cl)=[N:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:34]([C:36]2[S:40][C:39]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[N:38][CH:37]=2)=[O:35])[CH2:31][CH2:32][CH2:33]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: O=C(c1cnc(Cl)s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)s2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 120 °C
Yield: 74.9 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (159 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole (152 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 120° C. in a microwave reactor for 1 hour. The mixture was cooled to RT and ambient pressure, the acetonitrile evaporated in vacuo, the residue partitioned between water (25 mL) and ethyl acetate (50 mL), the organic layer washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired product (181 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:27]2[CH2:28][CH2:29][N:24]([C:16]3[C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][C:19]([CH:21]4[CH2:23][CH2:22]4)=[CH:18][N:17]=3)[CH2:25][CH2:26]2)=[O:8])=[CH:9][CH:10]=1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: Cc1nc(Br)ccc1C(=O)O
Product: Cc1nc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 56.3 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (604 mg) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (816 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (695 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C1(C)C=CC(S(O[CH2:39][C@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[C:25]([O:24][C:22]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]2[C:18]([O:19][CH2:39][C@H:40]3[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]3)=[CH:17][CH:16]=[C:15]([F:20])[C:14]=2[Cl:21])[CH3:12])=[CH:9]1)=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](c1c(OC[C@H]2COC(C)(C)O2)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 110 °C

Procedure:
A suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (82.9 mg, 0.176 mmol), (R)-(−)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (77.8 mg, 0.272 mmol), and potassium carbonate (102.5 mg, 0.7416 mmol) in DMF (3 mL) was subjected to microwave heating [Biotage, 110° C.] for 90 min. EtOAc was added to dilute the reaction mixture and a standard aqueous workup was performed. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf 5 g] and purified using the Teledyne/ISCO system [RediSepRf silica 12 gram GOLD column], eluting with a solvent system of 5-20% EtOAc:heptane. Fractions containing product were combined and concentrated in vacuo. The recovered material was dissolved in minimal MeOH, passed through a syringe filter, and purified a second time by MDP, under acidic conditions (formic acid). Fractions were combined and concentrated in vacuo, giving the title material as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=8.42 (d, J=2.3 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.01 (dd, J=9.1, 8.3 Hz, 1H), 6.70 (dd, J=9.1, 4.0 Hz, 1H), 4.91 (q, J=6.8 Hz, 1H), 4.01-4.18 (m, 2H), 3.81-3.89 (m, 1H), 3.78 (dd, J=7.7, 4.9 Hz, 1H), 3.73 (br s, 1H), 1.73 (d, J=7.1 Hz, 3H), 1.68 (s, 9H), 1.34 (d, J=14.9 Hz, 6H). MS (ES+): m/z 604.96/606.80/608.57 (21/100/24) [MH++Na]. HPLC: tR=4.13 min (ZQ3, nonpolar—5 min).
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][C:4]([CH3:12])([O:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1.S(=O)(=O)(O)O.[C].[C].[OH-].[Na+].[Na]>O>[C:14]([O:13][CH:2]([CH3:1])[CH2:3][C:4]([CH3:12])([O:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5])(=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18]
Reactant: CC(O)CC(C)(C)OOC(C)(C)C
Reactant: O=C1C=CC(=O)O1
Agent: O=S(=O)(O)O
Agent: [C]
Agent: [Na+]
Solvent: O
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 100 mL 3-neck flask equipped with a magnetic stirrer, a thermometer and a condenser was charged with 21.1 g (0.10 mole) of 90.7% 1,3-dimethyl-3-(t-butylperoxy) butanol, 12.5 g (0.125 mole) of maleic anhydride and 6 drops of aqueous 50% sulfuric acid solution. The stirred reaction mixture was then heated to and held at 55°-65° C. for about 6 hours after which the reaction mixture was cooled to room temperature and poured into 100 mL of water. The organic layer that resulted was extracted with 200 mL of methyl t-butyl ether and the methyl t-butyl ether solution was washed with 100 mL of water at 30°-35° C. The resulting solution was dried over about 10% by weight of anhydrous MgSO4. The spent desiccant was separated by filtration and the solvent was removed in vacuo leaving 12.2 g (42% of theory, uncorrected) of a liquid product. An infrared spectrum of the product showed a small OH band, an anhydride carbonyl band at about 1785 cm-1, a strong ester carbonyl band at ca 1740 cm- 1 and a carbon-carbon double bond band at ca. 1650 cm-1. The product was then poured into 100 mL of aqueous 3% NaOH solution, stirred for 5 minutes at 20°-25° C. in order to prepare the sodium salt of the title product and to hydrolyze the excess maleic anhydride. The salt solution was extracted twice with 100 mL portions of pentane in order to remove neutral impurities. The salt solution was then brought to a pH of 2-3 with dilute hydrochloric acid solution and the resulting mixture was extracted twice with 100 mL portions of methyl t-butyl ether and the methyl t-butyl ether extracts were combined. The resulting solution was dried over about 10% by weight of anhydrous MgSO4 the spent desiccant was separated by filtration and the solvent was removed in vacuo leaving 11.2 g (39% of theory, uncorrected) of a light yellow liquid product. A liquid chromatography scan showed a major peak which indicated ca. 96% product purity according to area percent. The liquid chromatography scan of the product also showed that it contained a minor amount of 1,3-dimethyl-3-(t-butylperoxy)butanol, one of the reactants. Based on the liquid chromatographic purity the corrected yield for the product was ca. 37%. Analysis of the product by differential scanning calorimetry (DSC) showed a major peroxide decomposition exotherm at about 170° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([NH:11][C:12](=[NH:21])OC1C=CC=C(C)C=1)#[N:10].[Cl-].[Na+]>C(O)(C)C>[C:9]([NH:11][C:12]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[NH:21])#[N:10]
Reactant: Cc1cccc(OC(=N)NC#N)c1
Reactant: NCc1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#CNC(=N)NCc1ccncc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
4-Amino methyl pyridine (16.22 g) is added to a stirred suspension of N-cyano-O-(m-cresyl)pseudourea (27.51 g) in 200 ml of isopropanol. The mixture is heated to boiling and refluxed for five hours. The reaction mixture is filtered and the filtrate evaporated under reduced pressure. The residue is stirred in 250 ml of chloroform overnight, the solvent removed under reduced pressure, treated with 250 ml of diethyl ether, the ether decanted and the residual gum treated with 200 ml of 5% HCl and stirred at room temperature for one hour. The mixture is filtered, extracted twice with 200 ml portions of diethyl ether and cooled to about 5° C. The solution is treated carefully with a 50% aqueous sodium hydroxide solution to a pH of 9 and extracted twice with 250 ml portions of methylene chloride. The organic extracts are combined, dried, filtered and evaporated to dryness under reduced pressure leaving a small amount of colored liquid. The aqueous layer is saturated with sodium chloride and re-extracted. After drying, the extracts are evaporated under reduced pressure. The aqueous phase is concentrated under reduced pressure and diluted with ethanol. The precipitated salts are removed by filtration and the filtrate concentrated under reduced pressure. The residue is azeotroped with 150 ml of toluene. The residue is stirred with 250 ml of isopropanol, filtered and evaporated under reduced pressure. The residue is triturated with 250 ml of isopropanol and filtered. The filtrate is dried, filtered, and evaporated under reduced pressure. The residue is taken up in a methanol/ethyl acetate mixture and allowed to stand. After trituration, the mixture is stirred in water overnight, the precipitate then collected and dried in air. The off-white solid is recrystallized from water yielding 12.10 g of pale yellow crystals which are dried in vacuo (55° C.), MP 92°- 93° C. IR and elemental analysis indicate the desired guanidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([S:34]([NH:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][N:39]=3)(=[O:36])=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.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].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][C:8]=1[C:24]1[C:33]2[C:28](=[CH:29][C:30]([S:34]([NH:37][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][N:39]=3)(=[O:35])=[O:36])=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COc1cc(-c2nccs2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(-c2nccs2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.127 g, 0.156 mmol), 2-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole (Intermediate OOOOO; 0.643 g, 2.026 mmol), 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate GG) (0.500 g, 1.559 mmol), and potassium carbonate (0.862 g, 6.24 mmol) in 6 mL dioxane/2 mL water was heated to 110° C. for 2 hours. LC/MS showed mostly product, so the reaction mixture was allowed to cool to room temperature. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane) (1.559 ml, 6.24 mmol). After stirring for an additional 10 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(2-methoxy-4-(thiazol-2-yl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.507 g, 1.066 mmol, 68.4% yield). 1H NMR (MeCN-d3) δ: 8.71 (d, J=5.7 Hz, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=6.3 Hz, 1H), 7.91-7.97 (m, 3H), 7.75-7.84 (m, 2H), 7.72 (sd, J=7.8 Hz, 1H), 7.60 (d, J=3.2 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.06 (s, J=6.3 Hz, 1H), 3.75 (s, 3H); (M+H)+=476.0.