Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18][S:19]([N:22]([CH2:24][CH:25]4[CH2:30][O:29][CH2:28][CH2:27][O:26]4)[CH3:23])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[O:26]1[CH2:27][CH2:28][O:29][CH2:30][C@H:25]1[CH2:24][N:22]([CH3:23])[S:19]([NH:18][C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1)(=[O:21])=[O:20]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN(CC1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: CN(C)C=O
Product: CN(C[C@@H]1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 135 °C

Procedure:
N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide (0.500 g, 1.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.692 g, 3.33 mmol), Pd2(dba)3 (0.051 g, 0.056 mmol), (tBu3)PBF4 (0.032 g, 0.11 mmol) and potassium fluoride (0.212 g, 3.66 mmol) were combined in a dry tube. 5 mL dry DMF was added and argon was bubbled through the solution for five minutes. The tube was sealed and heated in the Biotage Initiator series microwave to 135° C. for 20 minutes. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, and brine. The organic layer was dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by silica chromatography (0-100% ethyl acetate/hexanes gradient followed by 0-10% methanol/dichloromethane gradient) to afford the crude compound. The crude material was crystallized from a mixture of 10 mL methanol, 40 mL dichloromethane, and 70 mL hexanes to afford the title compound. 1H NMR (600 MHz, D6-DMSO) δ 10.52 (s, 1H); 9.20 (d, 1H); 8.55 (d, 1H); 8.45 (s, 1H); 8.13 (s, 1H); 7.95 (d, 1H); 7.75 (d, 1H); 7.55 (d, 1H); 7.32 (d, 1H); 7.22 (d, 1H); 3.88 (s, 3H); 3.64-3.60 (m, 2H); 3.58-3.54 (m, 1H); 3.54-3.50 (m, 1H); 3.44-3.40 (m, 1H); 3.38-3.34 (m, 1H); 3.14-3.10 (m, 3H); 2.77 (s, 3H). LRMS (APCI) calc'd for (C24H26N5O5S) [M+H]+, 496.2; found, 496.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][C:60]([C:63]2([NH2:66])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:66][C:63]3([C:60]4[CH:61]=[CH:62][C:57]([C:56]([F:55])([F:67])[F:68])=[CH:58][CH:59]=4)[CH2:65][CH2:64]3)=[O:21])=[CH:22][CH:23]=2)[N:10]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2ccc(C(F)(F)F)cc2)CC1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.290 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.193 g, 0.590 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.073 g, 0.350 mmol) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 4H), 7.36 (d, J=7.8 Hz, 2H), 7.46-7.70 (m, 5H), 8.01 (s, 4H), 9.30 (s, 1H), 12-13 (br s, 1H); MS (m/z): 515.23 (M−H)−.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O.CCOC(C)=O>[Br:1][C:14]1[S:13][C:12]([NH2:15])=[N:11][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1
Reactant: Nc1nc(-c2ccc(F)cc2)cs1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccc(F)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 0.01 h

Procedure:
Bromine was added to a solution of 4-(4-fluoro-phenyl)-thiazol-2-ylamine (12 g, 62 mmol) in acetic acid at room temperature. The mixture was stirred at room temperature for 30 sec and solidified. The mixture was diluted with water and poured to ice-water. The light grey suspension was filtered. The solid obtained was taken up in EtOAc and carefully basified with aqueous K2CO3 (pH was adjusted to 8˜9). The EtOAc extract was dried over MgSO4 and concentrated to give crude 5-bromo-4-(4-fluoro-phenyl)-thiazol-2-ylamine (15.15 g). This was then mixed with 4-fluorophenol (6.9 g, 62 mmol) and Cs2CO3 (22 g, 68 mmol) in acetonitrile (120 mL) and heated at 70° C. for 2 h and concentrated. The residue was partitioned between EtOAc and water. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound with some impurities. m/z 305.1 (MH+).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].S(OC)(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=O)[CH2:27]2>CCCCCC>[CH3:2][O:4][C:20]12[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[C:21]1=[CH:30][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)[CH2:29]2
Reactant: COc1cccc(C(=O)C2C3CC4CC(C3)CC2C4)c1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Product: COc1cccc(C=C2C3CC4CC(C3)CC2(OC)C4)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A quantity (11.3 g, 0.042 mol) of 3-methoxyphenyl adamant-2-yl ketone obtained according to Example 1 was suspended in 90 ml of molecular sieve-dried (3 Å) dimethylsulfoxide (DMSO). Heat was applied to dissolve the suspended solid. Upon cooling to room temperature with stirring, a fine suspension was formed. Potassium tertbutoxide (8.5 g, 0.070 mol) was added under an argon atmosphere. After 5 minutes, a nearly homogenous orange solution resulted, which was placed in a water bath at 50° C. Dimethyl sulfate (4 ml, 0.042 mol) was added dropwise by syringe over a period of 10 minutes. After 15 minutes of further stirring, an additional 3.3 ml of dimethyl sulfate (0.034 mol) was added in the same fashion. Subsequently, the colorless solution was stirred overnight at room temperature. After cooling in an ice bath, 0.5 g of K2CO3 and 125 ml of ice water added and the mixture extracted with three 50 ml portions of ethyl acetate. The combined organic fractions were washed with three portions of water, once with 50 ml of saturated aqueous NaCl solution, and dried over K2CO3. The solvent was removed in vacuo to yield an oil. The oil was dissolved in hexane, and the resulting solution filtered through Celite and concentrated in vacuo to provide 11.5 g (96% yield) of a viscous, straw-colored oil substance. TLC indicated a clean conversion to an enol ether (Rf 0.68; E. Merck Al2O3 --CH2Cl2 : hexanes - 50:50) with a trace of the ketone starting material. The oil was distilled from K2CO3 (b.p. 148-150° C., 0.25 mm Hg). Under these conditions, slight yellowing occurred in the still head. I.R. analysis of this distillate revealed a small ketone absorption band at 1670 cm31 1. I.R. (CH2Cl2): 2900 cm-1, 1670 cm-1 (weak), 1600 cm-1, 1590 cm-1, 1580 cm-1, 1570 cm-1, 1095 cm-1, 1080 cm-1 ; 1H-NMR 60 MHz (CDCl3): δ 1.5-2.0 (m, 12H), δ 2.55 (s, 1H), δ 3.2 (s, 1H), δ 3.25 (s, 3H), δ 3.75 (s, 3H), and δ 6.7-7.3 (m, 4H). These data confirmed that the structure of the product was: ##STR31##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([C:30]([F:31])([F:32])[F:33])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:29])[CH3:28]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Yield: 81.4 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(3-fluorophenyl)methyl]-1-indanol (98% trans, 2% cis) and 1.07 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.52 g of trans-3-[(3-fluorophenyl)methyl]-1-indanyl cis-3(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:20]N1C(=O)CCC1=O.O>ClCCl>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCn2ccc(C(N)=O)c2C1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)cc(C(N)=O)c2C1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution under nitrogen of 21.1 g (79.6 mmol) of tert-butyl 8-carbamoyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 600 ml of dichloromethane, cooled to −40° C., is added dropwise a solution of 10.6 g (79.6 mmol) of N-chlorosuccinimide in 200 ml of dichloromethane over about 40 minutes. Stirring is continued for 6 hours at a temperature of −40° C., 150 ml of water are then added and the reaction medium is allowed to warm to room temperature. The product is isolated by filtration and is washed with water to give 17.5 g of tert-butyl 8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a whitish solid after drying under reduced pressure at 40° C. in the presence of phosphorus pentoxide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1Br)[C:18](=[O:23])[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:25]([N:27](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:25]#[N:27])[C:18](=[O:23])[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COCc1ccccc1)Nc1cc2c(cc1Br)C(=O)CC2
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cc2c(cc1NC(=O)COCc1ccccc1)CCC2=O
Temperature: 85 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A 12 L, 4 neck flask was equipped with an overhead stirrer, an N2 inlet, a type-J Teflon® covered thermocouple, solid addition funnel, and a reflux condenser. The flask was charged with 2-benzyloxy-N-(6-bromo-I-oxoindan-5-yl)acetamide (2000 g, 5.35 mol), as is weight uncorrected for a purity of about 85-90%) and DMAC (3320 ml). Nitrogen was bubbled through the resulting dark viscous solution for 40 minutes. To this stirring solution was added Pd2(dba)3 (52.4 g, 57.0 mmol) followed by DPPF (58.4 g, 105 mmol). The resulting slurry was then heated to 85° C. and was treated with solid Zn(CN)2 (372 g, 3.18 mol) portion-wise over a period of 2 hours. The reaction was stirred at 85° C. for 3 hours. At that time the reaction was judged to be complete (by LC and TLC) and was then allowed to cool to 20° C. and stir overnight at that temperature under an atmosphere of N2. The following morning the reaction mixture was split into two equal portions. Each half was diluted with 12 L of water resulting in the formation of a yellow precipitate. The yellow solid from each portion was collected by vacuum filtration rinsing with water (12 L) followed by IPA (500 ml). The combined solids were allowed to air dry in a fume hood to afford 1701 g (1225 g, 85% yield-corrected for a product purity of 72% by weight and a starting material purity of 85%) of a yellow powder. This material was used directly in the next step without purification. TLC Analysis: Rf=0.28 (50% EtOAC/hexanes). HPLC 10:90 to 90:10 CH3CN:H2O over 15 min. Hold at 90:10 for 2 min, 0.025% TFA Buffer, 1.5 mL/min, UV at 220 nm, Phenomenex Jupiter C18 column 4.6 mm×250 mm at 29° C.: (11.68 min, 93 A %) 1H NMR (CDCl3, 300 MHz): 2.70-2.76 (m, 2H), 3.16-3.23 (m, 2H), 4.16 (s, 2H), 4.74 (s, 2H), 7.32-7.45 (m, 5H), 7.98 (s, 1H), 8.69 (s, 1H), 9.30 (br, 1H).
Reaction SMILES: [O-]CC.[Na+].[CH:5]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)C.CCOCC>[CH:5]1([C:11](=[O:13])[CH:12]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(C=Cc1ccc(F)cc1)C1CCCCC1
Yield: 69.6 %

Procedure:
A sodium ethoxide solution (21% by weight in ethanol, 6.805 gm, 21 mmol) was added to a mixture of 1-cyclohexyl-1-ethanone (18.749 g, 140 mmol, from Aldrich) and 4-fluorobenzaldehyde (17.37g, 140 mmol, from Aldrich) in ethanol (100 ml), stirring under argon. The solution was allowed to stir 1.5 hours. The reaction mixture was then concentrated to afford an orange oil. The oil was dissolved in ether, washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered and concentrated to an orange oil. The oil was purified by distillation (bp =143° C. at 1.3 mm Hg). The resultant yellowish oil slowly solidified to afford the title compound as hard yellow crystals (22.640 gm, 65%).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1.[CH:27](OC)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[F:26][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([F:19])[C:25]=1[CH:27]=[O:28]
Reactant: COC=O
Reactant: Fc1cncc(F)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)cncc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and at −70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalent) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalent) in 23 ml of THF. The solution formed was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then brought to −70° C. and diluted with 23 ml of THF, and 11.5 g of 3,5-difluoropyridine (100 mmol, 1 equivalent) dissolved in 72 ml of THF, were added dropwise. The mixture was stirred at −70° C. for 30 min. 12.4 ml of methyl formate (200 mmol, 2 equivalent), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at −70° C., the reaction solution was quickly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. This gave 11.6 g (81% of theory) of the title compound which were directly reacted further.
Reaction SMILES: N([O-])=O.[Na+].CS(O)(=O)=O.N[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[CH:16]2.C(#N)C.[I-:33].[Na+]>O.Cl.ClCCl>[I:33][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[CH:16]2
Reactant: [I-]
Reactant: Nc1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=N[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)c1cnc2c(I)cccc2c1
Reaction time: 0.08 h

Procedure:
A solution of sodium nitrite (5.44 g, 78.8 mmol, 1.2 eq) in water (125 ml, 5 vol) was added to a stirred slurry of 8-amino-3-phenylsulfonylquinoline methanesulfonic acid salt (D35) (25.0 g, 65.7 mmol) in 5M HCl (500 ml, 20 vol). The mixture was stirred at 23° to 24.5° C. for 1 hr 5 min then acetonitrile (200 ml, 8 vol) was added. After 10 min a solution of sodium iodide (14.8 g, 98.6 mmol, 1.5 eq) in water (125 ml, 5 vol) was added over 3 min, resulting in the formation of a brown mixture and the evolution of gas. The brown mixture was stirred at 25° C. to 23° C. for 1 hr 5 min then dichloromethane (500 ml, 20 vol) was added and the mixture was stirred for 5 min. The lower organic layer was removed and the aqueous layer was extracted with dichloromethane (125 ml, 5 vol). The combined organic layers were washed with 10% w/v sodium sulfite (125 ml, 5 vol) then concentrated under reduced pressure. The resulting mixture was filtered and the cake was washed with acetonitrile (2×25 ml) and dried in a 40° C. oven under reduced pressure to afford the title compound D6; yield 15.27 g, 59%, identical spectroscopically to that produced by the first method.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([SH:12])[NH:10][N:11]=2)[CH:2]=1.C(N(CC)CC)C.Cl[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:23]>CN(C=O)C>[Cl:31][C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][S:12][C:9]2[NH:10][N:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:8]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Sc1nc(-c2cccnc2)n[nH]1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CSc1nc(-c2cccnc2)n[nH]1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
The thiol intermediate prepared in Step B (101 mg, 0.567 mmol) was dissolved in DMF (2 ml) and triethylamine (0.24 ml, 1.7 mmol). 2,3′-dichloroacetanilide (116 mg, 0.567 mmol) was added and allowed to stir at room temperature overnight. The mixture was loaded directly onto an HPLC reverse phase column and purified by water to acetonitrile gradient in the presence of 0.1% trifluoroacetic acid. The aqueous phase was evaporated by lyophilization to yield the title compound as a fluffy white solid (166 mg, 85% yield). MS (ES) 346.5 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[N:12]=[C:11]([O:21][CH2:22][CH3:23])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CC([O-])(C)C.[K+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:22]([O:21][C:11]1[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:3]=[CH:4][C:5]=3[C:6]=2[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:12]=1)[CH3:23]
Reactant: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(N3CCOCC3)ccc12

Procedure:
100 mg (0.27 mmol) 7-bromo-4-ethoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole (Example 4), 164 μl (1.86 mmol) morpholine, 179 mg (1.59 mmol) KOt-Bu, 1.2 mg (5.4 μmol) Pd(OAc)2 and 4.4 mg (21.6 μmol) P(t-Bu)3 were heated in 6 ml toluene in a microwave oven to 140° C. for 3 h. Then, the solvent was removed and the residue was purified by preparative HPLC (RP18). 8 mg (8%) of the title substance was obtained. ESI-MS [m/z]: 383 [M+H]+
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:11][CH:10]([O:12][CH3:13])[CH2:9]2)=[N:6][CH:7]=1.[O:14]=[C:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:13][O:12][CH:10]1[CH2:11][N:8]([C:5]2[N:4]=[CH:3][C:2]([N:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16][C:15]3=[O:14])=[CH:7][N:6]=2)[CH2:9]1
Reactant: COC1CN(c2ncc(I)cn2)C1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC1CN(c2ncc(N3CCN(C(=O)OC(C)(C)C)CC3=O)cn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Dioxane (12 ml) was added to a mixture of 5-iodo-2-(3-methoxyazetidin-1-yl)pyrimidine (1.14 g), tert-butyl 3-oxopiperazine-1-carboxylate (941 mg), rel-(1R,2R)-N,N′-dimethyl cyclohexane-1,2-diamine (223 mg), copper iodide (149 mg), and potassium phosphate (2.5 g), followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature and then filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3-oxopiperazine-1-carboxylate (867 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:14])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:6][C:7]=1I)#[N:2].C[Sn](C)(C)[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I.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>[C:24]([NH:23][C:19]1[CH:18]=[C:17]([C:7]2[S:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([I:14])[C:3]=2[C:1]#[N:2])[CH:22]=[CH:21][N:20]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: CCOC(=O)c1sc(I)c(C#N)c1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)c(C#N)c1I
Temperature: 110 °C
Yield: 64.9 %

Procedure:
To a solution of ethyl 4-cyano-3,5-diiodothiophene-2-carboxylate (0.473 g, 1.09 mmol) and N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.392 g, 1.31 mmol) in dioxane (10.2 mL) was added lithium chloride (0.139 g, 3.28 mmol), copper(I) iodide (0.0624 g, 0.328 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0947 g, 0.0819 mmol). The reaction flask was evacuated and backfilled with argon, then the solution was heated at 110° C. for 2 hours. The mixture was cooled to room temperature and a mixture of dichloromethane and methanol was added until almost all solids had dissolved. The suspension was filtered through celite and the filtrate was evaporated. Column chromatography was performed to yield the title compound (0.312 g, 65%). LCMS: (FA) ES+ 442. 1H NMR (400 MHz, d6-DMSO) δ: 8.54-8.49 (m, 2H), 8.31 (s, 1H), 4.38-4.32 (m, 2H), 2.13 (s, 3H), 1.36-1.29 (m, 3H).