Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:4]([C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-methoxy-4-chlorobenzoic acid (1.0 g, 0.0054 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 0.00507 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.74 (s, 3H), 7.00 (d, J=1.77 Hz, 1H) 7.05 (dd, J=8.08, 1.77 Hz, 1H), 7.32 (d, J=8.08 Hz, 1H), 7.41-7.48 (m, 2H), 7.54-7.60 (m, 1H), 7.74-7.83 (m, 2H). MS (ES+): m/z 246.83 (100)[MH+]. HPLC: tR=3.66 min (Open Lynx polar—5 min).
Reaction SMILES: COC(OC)OC.[C:8](#N)C.[NH:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:29]([C:35]([NH:37][NH2:38])=O)=[N:30][CH:31]=[C:32]([Cl:34])[CH:33]=2)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:39]([F:42])([F:41])[F:40]>C(O)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:29]([C:35]3[N:16]([C:14]4[CH:15]=[N:11][NH:12][CH:13]=4)[CH:8]=[N:38][N:37]=3)=[N:30][CH:31]=[C:32]([Cl:34])[CH:33]=2)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:39]([F:42])([F:41])[F:40]
Reactant: Nc1cn[nH]c1
Reactant: CC#N
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: O=S(=O)(Nc1cc(Cl)cnc1-c1nncn1-c1cn[nH]c1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to general Method B. Thusly, a mixture of trimethylorthoformate (53 mg, 0.50 mmol), acetonitrile (1.5 mL), and 1H-pyrazol-4-ylamine (83 mg, crude, 1.0 mmol) was stirred at 120° C. for 2 hours. After the mixture was cooled to room temperature, 4-Chloro-N-(5-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide (42.8 mg, 0.10 mmol) and acetic acid (0.2 mL) was added and the resultant mixture was stirred at 120° C. for 2 hours. After evaporation of solvent under reduced pressure, the residue was further purified through automated normal-phase chromatography and dried (Lyophilizer) to afford title compound. 1H NMR: (DMSO-d6, ppm): 8.90 (s, 1H), 8.08 (m, 2H), 7.90 (m, 2H), 7.80 (m, 2H), 7.75 (m, 1H). MS (ES) [M+H]+ expected 504.0, found 504.0.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=[O:15].[K+:17].[K+].C1C2C(=CC(C([O-])=O)=CC=2)C=CC=1C([O-])=O.[K+].C([O-])(=O)C1C(=CC=CC=1)C(O)=O>O>[K+:17].[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([O-:16])=[O:15]
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: O=C([O-])c1ccc2cc(C(=O)[O-])ccc2c1
Agent: O=C([O-])c1ccccc1C(=O)O
Agent: [K+]
Solvent: O
Product: O=C([O-])c1ccc2cc(C(=O)O)ccc2c1

Procedure:
A process for preparing 2,6-naphthalenedicarboxylic acid which comprises a) reacting 2,6-naphthalenedicarboxylic acid dipotassium salt with phthalic acid monopotassium salt in the presence of water at a temperature of 0°-200° C. to yield solid 2,6-naphthalenedicarboxylic acid monopotassium salt and an aqueous solution of a phthalic acid dipotassium salt; b) separating the solid 2,6-naphthalenedicarboxylic acid monopotassium salt from the aqueous solution containing phthalic acid dipotassium salt; c) reacting the 2,6-naphthalenedicarboxylic acid monopotassium salt with phthalic acid in the presence of water at 0°-200° C. to yield solid 2,6-naphthalenedicarboxylic acid and an aqueous solution of phthalic acid monopotassium salt; d) separating solid 2,6-naphthalenedicarboxylic acid from the aqueous solution containing phthalic acid monopotassium salt; and e) recycyling the aqueous solution containing phthalic acid monopotassium salt to step a).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:8][C@@H:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (S)-Methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)-methyl)benzoate (I12, 3.21 g, 7.20 mmol) in methanol (36 mL) was added hydrogen chloride in dioxane (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at RT for 16 h. The solvent was removed in vacuo to afford (S)-Methyl 4-((3-(amino(phenyl)methyl)phenoxy)methyl)benzoate hydrochloride (2.65 g, >95%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.[CH2:24]=O>C(#N)C.N1CCCC1C(O)=O>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:24][CH:19]1[C:20](=[O:21])[O:22][C:15]([CH3:23])([CH3:14])[O:16][C:17]1=[O:18])=[CH:5][NH:6]2
Reactant: Cc1c([N+](=O)[O-])ccc2[nH]ccc12
Reactant: C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])ccc2[nH]cc(CC3C(=O)OC(C)(C)OC3=O)c12
Yield: 63.5 %

Procedure:
An adaption of the procedure of Flaugh was used. Thus, a solution of 4-methyl-5-nitroindole (0.880 g, 5.00 mmol), Meldrum's acid (0.864 g, 6.00 mmol), 37% aqueous formaldehyde (0.5 mL, 6.0 mmol) and D,L-proline (0.029 g, 0.25 mmol) in 25 mL of acetonitrile was stirred at room temperature for 72 h. The resulting yellow slurry was stored at -20° C. and then the cold mixture was filtered. The filtercake was washed with cold acetonitrile and ether, and then it was dried in vacuo to give the title compound (1.055 g, 64%) as a canary-yellow solid, mp 196°-198° C. (dec): IR (KBr) 3338, 1782, 1742 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 11.46 (br s, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.25 (d, J= 2.4 Hz, 1H), 4.74 (t, J=5.0 Hz, 1H), 3.64 (d, J=4.9 Hz, 1H), 2.80 (s, 3H), 1.84 (s, 3H), 1.69 (s, 3H). Anal. Calcd for C16H16N2O6 : C, 57.83; H, 4.85; N, 8.43. Found: C, 57.42; H, 4.68; N, 8.52.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:23])[C@H:6]([NH2:22])[C:7]([O:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[O:8])(=[O:3])[CH3:2].ClCC(O)=O.[N:29]([O-])=O.[Na+].C(O)(=O)C>O>[C:1]([O:4][C@H:5]([CH3:23])[C:6](=[N+:22]=[N-:29])[C:7]([O:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH:12][C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)[C@H](N)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=N[O-]
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)C(=[N+]=[N-])C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
To a mixture of O-[3(R)-acetoxy-2(S)-amino-1-oxobutyl]-N-trifluoroacetyl-L-serine (200 mg) and chloroacetic acid (0.015 ml) in water (2ml) was added sodium nitrite (80 mg) at room temperature. After stirring for 0.5 hour at room temperature, acetic acid was added and the mixture was extracted with ethyl acetate (3 times) and the ethyl acetate extracts were combined and washed with brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on preparative thin layer chromatography to give O-[3(R)-acetoxy-2-diazo-1-oxobutyl]-N-trifluoroacetyl-L-serine (8 mg).
Reaction SMILES: [CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.O.C(OCC1C=CC=CC=1)[C@@H]1OC1>CC(O)=O.C1COCC1>[CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[C@H:2]1[O:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CO1
Agent: c1ccc(COC[C@H]2CO2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Yield: 48.3 %

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-(tert-butyldimethylsilyl) glycidyl ether (5.64 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-(tert-butyldimethylsilyl) glycidyl ether 5c (2.72 g, 14.5 mmol, 48%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 Torr). The product was determined to be present in >99% ee by derivatization through ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C. and direct analysis of the 2-napthylsulfide thus obtained (Chiralcel OD, 99.25:0.75 hexanes:EtOH, 1 mL/min, 230 nm).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:12]=[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][N:5]2[N:4]=1.[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:27])[C:23]=1[C:24](O)=[O:25])=[O:18])[CH3:15].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][N:2]([CH3:13])[C:3]1[N:12]=[C:6]2[CH:7]=[C:8]([NH:11][C:24]([C:23]3[N:22]([CH3:27])[N:21]=[CH:20][C:19]=3[C:17]([O:16][CH2:14][CH3:15])=[O:18])=[O:25])[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: CN(C)c1nc2cc(N)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)C)nc2c1
Yield: 89.3 %

Procedure:
A mixture of N2,N2-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2,7-diamine (700 mg, 3.95 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (812 mg, 4.1 mmol), propylphosphonic anhydride (50% in ethyl acetate, 5.82 ml, 9.88 mmol) and diisopropylethylamine (2.07 ml, 11.9 mmol) in tetrahydrofurane (40 ml) is refluxed for 18 hours under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The solid is collected by filtration, washed with water and dried affording ethyl 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (1.26 g, 89.3%) as a light brown solid. Mp.: 193-5° C. MS: m/z=358.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[C:10]([CH3:11])[CH:9]=3)=[O:8])[CH2:24][CH2:25]2)=[N:18][CH:19]=1)[CH3:13]
Reactant: Cc1cc(C(=O)O)cnc1F
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Yield: 39.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-5-methylnicotinic acid (500 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (661 mg) described in Preparation Example 53, the title compound (440 mg) was obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.FB(F)F.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][O:13][C:9]1[C:8]2[CH:4]=[CH:5][S:6][C:7]=2[CH:12]=[CH:11][CH:10]=1.[CH3:14][O:13][C:9]1[CH:10]=[CH:11][C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ccsc2c1
Product: COc1cccc2sccc12
Reaction time: 1 h
Yield: 16 %
Yield: 60 %

Procedure:
To the obtained (2,2-diethoxyethyl)(3-methoxyphenyl)sulfane (91, 3.6 g, 14.0 mmol) dissolved in a dichloromethane solution (70 mL) was slowly added trifluoroborane etherate (BF3-Et2O; 1.75 mL, 13.72 mmol) at room temperature under nitrogen, and the reaction mixture was stirred for one hour and neutralized with a sodium bicarbonate solution at room temperature. Organic layer was isolated, organic compounds in water were extracted with dichloromethane, the recovered organic solution was evaporated after a treatment with sodium sulfate, and concentrated under reduced pressure. After concentration, residues were purified by column chromatography to give the target compounds 4-methoxybenzothiophene (92a, 368 mg, 16%) and 6-methoxybenzothiophene compounds (92b, 1.38 g, 60%) as transparent liquids.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:23]3[N:22]=[C:21]([C:24]4[C:29](Br)=[CH:28][CH:27]=[CH:26][C:25]=4Br)[NH:20][C:19]=3[C:18]3[C:13](=[CH:14][C:15]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:16][CH:17]=3)[C:11]=2[CH:12]=1.[NH4+].[OH-].C(OCC)(=O)C.[CH3:44][N:45](C=O)C>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:23]3[N:22]=[C:21]([C:24]4[C:25]([C:4]#[N:5])=[CH:26][CH:27]=[CH:28][C:29]=4[C:44]#[N:45])[NH:20][C:19]=3[C:18]3[C:13](=[CH:14][C:15]([C:32]([OH:35])([CH3:33])[CH3:34])=[CH:16][CH:17]=3)[C:11]=2[CH:12]=1
Reactant: N#C[Cu]C#N
Reactant: CC(C)(O)c1ccc2c(c1)c1cc(Br)ccc1c1nc(-c3c(Br)cccc3Br)[nH]c21
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc2c(c1)c1cc(Br)ccc1c1nc(-c3c(C#N)cccc3C#N)[nH]c21
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
Copper cyanide (420 mg, 4.7 mmol) was added to a room temperature solution of 2-[6-bromo-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazol-9-yl]propan-2-ol from Step 4 (1.25 g, 2.1 mmol) in DMF (100 mL) and the mixture heated at 80° C. for 18 h, after which it was poured into a mixture of NH4OH and ethyl acetate and stirred for 1 h. The aqueous phase was extracted with ethyl acetate, the organic layer washed once with water, once with brine, dried over Na2SO4, filtered and concentrated. The material obtained after purification by flash chromatography on silica (20-80% ethyl acetate in toluene) was swished in ethyl acetate and THF for 2 h and then filtered to afford 2-[6-bromo-9-(1-hydroxy-1-methylethyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile as a yellow solid (250 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[Cl:30]C1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:30])=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: CS(=O)(=O)c1cc(Br)ccc1-c1ccc(Cl)cc1

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 4-chlorophenylboronic acid, the title compound was obtained as a beige solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[C:10](Cl)(=[O:12])[CH3:11].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 4,6-dichloro-pyrimidin-2-ylamine (5 g, 30 mmol) and acetyl chloride (4.7 g, 60 mmol) in acetic acid (200 mL) was stirred at 80° C. under nitrogen overnight. The solution was cooled to RT and water (150 mL) was added. The mixture was extracted with ethyl acetate (3×150 mL), and the combined organics were washed with brine, dried over sodium sulfate and concentrated to give N-(4,6-dichloro-pyrimidin-2-yl)-acetamide (5.0 g, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[Cl:11][C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl>[ClH:11].[S:8]1[C:4]2[CH:3]=[C:2]([NH:1][C:12](=[O:13])[O:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: Cl
Product: O=C(Nc1ccc2ncsc2c1)Oc1ccc([N+](=O)[O-])cc1
Yield: 78.1 %

Procedure:
6-Aminobenzothiazole (100 mg, 0.666 mmol) and p-nitrophenyl chloroformate (148 mg, 0.733 mmol) were stirred at rt in CH2Cl2 (5 mL) overnight. The resulting solid was collected by filtration, yielding 183 mg (81%) of the title compound. LC-MS: RT=8.17 min, [M+H]+=316.0
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]1[CH:16]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14][CH2:13][CH:12]1[C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1.O.[OH-].[Na+:34]>CO>[Na+:34].[CH3:30][C:29]1[C:24]([CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:11]2[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O-:31])=[O:2])=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1C(=O)[O-]
Temperature: 25 °C
Yield: 108.6 %

Procedure:
To a solution of 2-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.723 g, 1.74 mmol) in MeOH (5 mL) was added water (5 mL) and solid NaOH (0.757 g, 18.93 mmol). The resultant mixture was heated to reflux overnight then cooled to room temperature. The mixture was extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 0.80 g (97%) of COMPOUND 63 as a while solid. 1H NMR (D2O) δ 1.58-1.73 (m, 3H), 1.88-2.04 (m, 3H), 2.36 (s, 6H), 3.66 (s, 2H), 4.12 (d, 2H, J=10.2 Hz), 6.82 (t, 1H, J=7.2 Hz), 6.92-7.03 (m, 4H), 7.40-7.47 (m, 3H), 8.13 (d, 2H, J=3.9 Hz). 13C NMR (D2O) δ 16.66, 24.13, 32.40, 56.97, 65.27, 122.76, 125.65, 127.27, 128.10, 130.45, 132.60, 136.88, 139.70, 146.15, 159.77, 177.12; ES-MS m/z 402 (M+H), 424 (M+Na). Anal. Calcd. For C25H26N3O2Na.2.7H2O: C, 63.60; H, 6.70; N, 8.90. Found: C, 63.60; H, 6.78; N, 8.55.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C[N:23]([CH:25]=O)C.[NH2:27]N.O>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[C:9]=1[CH2:25][N:23]=[NH:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CC(C)(C)NC(=O)c1cc2c(s1)CCCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1sc2c(c1CN=N)CCCC2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 117a (100 g, 0.42 mol, 1.0 equiv) in THF (500 mL) was slowly to added n-BuLi (672 mL, 2.5M in THF, 1.68 mol, 4.0 equiv) at −78° C. under argon. The mixture was stirred for 2 h. DMF (306 g, 4.2 mol, 10.0 equiv) was added to the mixture while the temperature was maintained at −78° C. After another 2.0 h, the reaction was quenched with methanol (500 mL) at −78° C. It was stirred for 0.50 h at room temperature. 80% aqueous hydrate hydrazine (131 g, 2.1 mol) was added and the mixture was refluxed at 65° C. overnight. The organic solvent was removed under reduced pressure. The residue was filtered and the yellow solid collected was washed with water. The solid was dried in vacuo to afford crude 117b, which was used in the next step without further purification. MS: [M+H]+ 280.
Reaction SMILES: C(C1C=C([C:9]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][N:12]3[N:13]=[C:14]4[C:19]([CH:18]=[CH:17][C:16]([C:20]5[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=5)[C:23]#[N:24])=[CH:15]4)=[C:11]3[N:10]=2)C=CC=1)#N.[C:36]([O:40][C:41](=[O:62])[NH:42][C:43]1([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[C:36]([O:40][C:41](=[O:62])[NH:42][C:43]1([C:47]2[CH:48]=[CH:49][C:50]([C:9]3[C:29]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][N:12]4[N:13]=[C:14]5[C:19]([CH:18]=[CH:17][C:16]([C:20]6[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[CH:21]=6)=[CH:15]5)=[C:11]4[N:10]=3)=[CH:51][CH:52]=2)[CH2:44][CH2:45][CH2:46]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: N#Cc1cccc(-c2ccc3c(c2)nn2cc(-c4ccccc4)c(-c4cccc(C#N)c4)nc32)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5ccc(-c6cccc(C#N)c6)cc5nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
179 mg of the mixture described in step 1,3-(2-chloro-3-phenylpyrimido[1,2-b]indazol-8-yl)benzonitrile and the byproduct 3-[2-(3-cyanophenyl)-3-phenyl-pyrimido[1,2-b]indazol-8-yl]benzonitrile, 210.5 mg (0.56 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, 38.4 mg (0.047 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 0.87 mL aqueous sodium carbonate solution (10%) in 1.6 mL dimethoxyethane were heated in the microwave oven for 60′ at 120° C. After the usual work up described in step 1, the mixture (239.4 mg) was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][O:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:48]3[CH2:49][CH2:50][CH:45]([O:44][CH3:43])[CH2:46][CH2:47]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC1CCNCC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: COC1CCN(C(=O)c2noc3c(F)c(N4C[C@@H](C)O[C@@H](C)C4)c(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)CC1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 4-methoxypiperidine