Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19].[CH2:22]([O:24][C:25](=[O:28])[NH:26][NH2:27])[CH3:23].CC1C=CC(S(N)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[N:27][NH:26][C:25]([O:24][CH2:22][CH3:23])=[O:28])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: CCOC(=O)NN
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Agent: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=C(C)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 150 °C
Reaction time: 40 h
Yield: 40.5 %

Procedure:
In a round bottom flask fitted with a Dean-Stark, a solution of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (2.384 g, 7.86 mmol) in toluene (16 mL) was treated with ethylcarbazate (2.61 g, 25 mmol,) followed by p-toluenesulfonamide (103 mg, 0.60 mmol). The reaction was stirred at 150° C. for 40 h. The solvent was removed by distillation and the residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to give the title compound (1.24 g, 40%). API-ES: m/z 390.1 [M+H]+, rt 4.14 min, 4.20 min: mixture of cis and trans.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[NH:22][N:21]=2)[C:16]([Cl:31])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:31][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: FC(F)(F)COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(OCC(F)(F)F)[nH]n2)n1)c1ncc(F)cn1
Temperature: 165 °C
Yield: 59.6 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 81 mg, 0.46 mmol), 2,5-dichloro-N-[5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-yl]pyrimidin-4-amine (Method 40, 100 mg, 0.31 mmol), and DIEA (110 mg, 0.9 mmol). Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (80 mg, 62%). LC-MS, 433 (M+1). 1H NMR δ 12.19 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H), 7.92-8.10 (m, 2H), 5.67 (s, 1H), 5.13 (s, 1H), 4.75 (m, 2H), 1.49 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].[C:14](Cl)(Cl)=[S:15].[Cl:18][C:19]1[C:20]([N:25]=[C:26]=[S:27])=[N:21][CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([N:25]=[C:26]=[S:27])=[N:21][CH:22]=[CH:23][CH:24]=1.[Cl:8][C:7]1[C:2]2=[N:1][C:26](=[S:27])[N:25]([C:20]3[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=3)[C:14](=[S:15])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: S=C=Nc1ncccc1Cl
Agent: [Ca+2]
Product: S=c1nc2c(Cl)cccn2c(=S)n1-c1ncccc1Cl
Reaction time: 8 h

Procedure:
Following the procedure of Example 5, 6.4 g. of 2-amino-3-chloropyridine, 11 g. of calcium carbonate and 6.3 g. of thiophosgene is converted into 3-chloro-2-pyridylisothiocyanate b.p. 86° C. at 0.25 mm. of Hg. Upon standing overnight, the freshly distilled 3-chloro-2-pyridylisothiocyanate solidifies affording 9-chloro-3-(3-chloro-2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 120°-122° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[S:15][CH:16]=[C:17]([C:18]4[NH:22][N:21]=[C:20]([NH:23][C:24]5[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=5)[CH:19]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl-].[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[S:15][CH:16]=[C:17]([C:18]4[NH:22][N:21]=[C:20]([NH:23][C:24]5[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=5)[CH:19]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc3c(-c4cc(Nc5ccc(S(N)(=O)=O)cc5)n[nH]4)csc23)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: NS(=O)(=O)c1ccc(Nc2cc(-c3csc4c(-c5cccc(O)c5)cccc34)[nH]n2)cc1
Temperature: 180 °C
Yield: 68.9 %

Procedure:
4-{5-[7-(3-Methoxy-phenyl)-benzo[b]thiophen-3-yl]-1H-pyrazol-3-ylamino]-benzenesulfonamide (130 mg, 0.27 mmol) and pyridinium chloride (1.3 g) were combined in a sealed tube and heated at 180° C. for 2 h. The reaction was cooled, quenched with saturated NaHCO3 solution until the solid clump was broken up, and extracted with EtOAc (60 mL). Organics were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 86 mg (68%) of 4-{5-[7-(3-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-1H-pyrazol-3-ylamino]-benzenesulfonamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ12.67 (s, 1H), 9.72 (s, 1H), 9.13 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.58-7.67 (m, 3H), 7.45-7.51 (m, 3H), 7.36 (t, 1H, J=7.8 Hz), 7.06-7.14 (m, 4H), 6.87 (d, 1H, J=7.5 Hz), 6.33 (s, 1H). Anal. (C23H18N4O3S2.0.1 H2O) C, H, N, S. Calculated C=59.49; H=3.95; N=12.07; S=13.81; found C=59.51; H=3.95; N=12.20; S=13.63.
Reaction SMILES: C12OC3CC([O:9]1)C(C=C3)C2.C(=O)(O)[O-].[K+].[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OO>CO.C(Cl)Cl>[C:16]([NH2:23])(=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccccc1
Reactant: C1=CC2CC3OC1CC2O3
Agent: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccccc1
Reaction time: 10 h

Procedure:
To a solution of 165 mg of racemic 9,10-dioxatricyclo[4,3,1,03,8 ]dec-4-ene in 4 ml of methanol are added, with stirring and at room temperature 865 mg of potassium bicarbonate and 740 mg of benzonitrile. To this mixture are added at intervals of 8 hours 5 portions each of 0.3 ml of 30% hydrogen peroxide and stirring is continued for 10 hours. Methylene chloride (25 ml) is then added to the reaction mixture, which is washed with 2% sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated. Benzamide which has formed is removed by crystallisation from methylene chloride/pentane. The residual oil can be used directly in the next reaction, or chromatographed on 22 g of basic aluminium oxide (activity level IV). Elution with petroleum ether/benzene (7:3) yields the racemic mixture of 4β,5β-epoxy-9,10-dioxatricyclo[4,3,1,03,8 ]decane of the formula ##SPC18##
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: COc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-methoxybenzylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:17][C:18](=[O:20])C)C=CC=CC=1>C1COCC1>[O:20]=[C:18]([CH3:17])[CH:2]=[CH:3][C:4]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5]1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCC1(CC=O)CC1
Solvent: C1CCOC1
Product: CC(=O)C=CC1(CC#N)CC1
Yield: 92.1 %

Procedure:
A mixture of the aldehyde from Example 1, Step 2 (8.12 g, 75 mmol) and 1-triphenylphosphoranylidene-2-propanone (26.4 g, 83 mmol) in 250 mL THF was heated to reflux overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate, and the organic layer was washed with brine, dried over MgSO4 and evaporated. Et2O was added to the residue, the phosphine oxide was filtered off and the solvent removed in vacuo. Purification through a plug of silica gel provided 10.3 g of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:24]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
Example 148 was prepared from N-(3-bromopropyl)-2,2-diphenyl acetamide and 2-methyl-N-[4-(4-piperidinyl) phenyl]propanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][N:9]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:32]=[CH:31][C:7]([CH2:8][N:9]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C1NCCCCC1N(Cc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
Rac-4-trifluoromethyl-benzenesulfonic acid (4-nitro-benzyl)-(2-oxo-azepan-3-yl)-amide (2.08 g, 4.4 mmol) was dissolved in methanol (50 ml), palladium on charcoal (200 mg, 10%) was added and the mixture was hydrogenated at room temperature for 2 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was recrystallised from heptane/ethyl acetate to yield a yellowish solid (1.2 g, 61%).
Reaction SMILES: FC(F)OC1C=CC([C@@H](NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)C)=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:42][CH:43]([F:72])[O:44][C:45]1[CH:50]=[CH:49][C:48]([C@@H:51]([N:53]2[CH2:58][CH2:57][C:56]3([CH2:70][CH2:69][C:61]4(OCC(C)(C)C[O:62]4)[CH2:60][CH2:59]3)[O:55][C:54]2=[O:71])[CH3:52])=[CH:47][CH:46]=1>>[F:72][CH:43]([F:42])[O:44][C:45]1[CH:50]=[CH:49][C:48]([C@@H:51]([N:53]2[CH2:58][CH2:57][C:56]3([CH2:70][CH2:69][C:61](=[O:62])[CH2:60][CH2:59]3)[O:55][C:54]2=[O:71])[CH3:52])=[CH:47][CH:46]=1
Reactant: C[C@@H](c1ccc(OC(F)F)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(OC(F)F)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-difluoromethoxy-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(4-difluoromethoxy-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound, too. Yield: 45% of theory; LC (method 6): tR=1.14 min; Mass spectrum (ESI+): m/z=354 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[C:17]([N:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10](=[O:12])[NH:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]1=2)(=[O:20])[CH:18]=[CH2:19]
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: C=CC(=O)Cl
Solvent: Cc1ccccc1
Product: C=CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
5.26 gm (0.025 mol) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2.7 gm (0.03 mol) of acrylic acid chloride were refluxed in 200 ml of toluene for 3 hours. Subsequently, the reaction mixture was evaporated in vacuo to dryness, and the residue was stirred with aqueous sodium bicarbonate solution. After suction-filtering, washing with water, and drying, 5-acryloyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one was obtained with a quantitative yield. Recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Br:57][C:58]1[CH:59]=[C:60]([C:64]2([NH2:68])[CH2:67][CH2:66][CH2:65]2)[CH:61]=[CH:62][CH:63]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.CC(=O)OCC>[Br:57][C:58]1[CH:59]=[C:60]([C:64]2([NH:68][C:21]([C:20]3[C:14]4[C:15](=[N:16][CH:17]=[C:12]([C:6]5[C:5]6[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=6)[N:8]([CH3:11])[N:7]=5)[N:13]=4)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=3)=[O:22])[CH2:67][CH2:66][CH2:65]2)[CH:61]=[CH:62][CH:63]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: NC1(c2cccc(Br)c2)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(c4cccc(Br)c4)CCC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Yield: 80 %

Procedure:
To a stirred suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (200 mg, 0.45 mmol) in DMF (5 mL) were added HATU (344 mg, 0.91 mmol) and 1-(3-bromo-phenyl)-cyclobutanamine hydrochloride (178 mg, 0.68 mmol) followed by DIPEA (0.40 mL, 2.26 mmol) at room temperature under nitrogen atmosphere. The resulting light yellow solution was stirred for 15 h by which time TLC analysis (Hex:EA, 1:1, Rf=0.5) indicated the presence of a new spot. Then, the reaction mixture was diluted with water and the organic compound was extracted into EtOAc (3×25 mL). The combined extracts were washed with brine solution and then dried over anhydrous MgSO4. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified using by ISCO column chromatography (40 g) eluting with EtOAc in hexanes (0-60%) in 10 minutes. The desired fractions were combined and the solvent was removed under vacuum to obtain 234 mg (80%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(3-bromophenyl)-cyclobutyl]-amide as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](Cl)([Cl:18])[C@@H:14]2[C:20]2[CH:25]=[CH:24][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1)=[O:4].C(N=C(N(C)C)N(C)C)(C)(C)C.Cl>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([Cl:18])=[C:14]2[C:20]2[CH:21]=[CH:22][C:23]([CH:26]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(Cl)Cl)cc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: ClCCCl
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(Cl)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 70 h

Procedure:
A solution of dichloride 4 (12 mg, 0.019 mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 0.2 mL) in 1,2-dichloroethane (0.5 mL) was stirred at 60° C. After 70 h, 1 M HCl (28 mL) was added and the mixture was extracted with 20 mL CH2Cl2. The dichloromethane solution was washed further with 1 M HCl (3×25 mL) and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (0% 15% ethyl acetate/hexanes) gave the title compound, contaminated with 15% of the alkene regioisomer 6b as an inseparable mixture (10 mg, 93%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: Brc1cnc2ccc(NC3CCOCC3)nn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: COCCOC
Product: NCc1ccc(-c2cnc3ccc(NC4CCOCC4)nn23)cc1
Temperature: 160 °C
Yield: 18.6 %

Procedure:
A mixture of 3-bromo-N-(tetrahydro-pyran-4-yl)imidazo[1,2-b]pyridazin-6-amine (100 mg, 0.34 mmol), 4-(aminomethyl)phenylboronic acid hydrochloride (160 mg, 0.84 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (25 mg, 0.034 mmol), potassium phosphate (360 mg, 1.7 mmol), DME (1.5 mL) and H2O (0.5 mL) was heated in a sealed conical vessel at 160° C. for 360 s by microwave irradiation. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic layers were concentrated under reduced pressure to afford an oil that was purified by reverse phase HPLC to afford [3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-(tetrahydro-pyran-4-yl)-amine (20.5 mg, 20%) as a yellow solid: 1H NMR (400 MHz, MeOD) δ 8.24 (d, J=8.4 Hz, 2H), 7.82 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.74 (d, J=10 Hz, 1H), 4.13 (s, 2H), 4.06-3.92 (m, 3H), 3.61 (t, J=11.2 Hz, 2H), 2.15 (d, J=12.8 Hz, 2H), 1.65 (qd, J=11.2, 4.4 Hz, 2H); LCMS (ESI) m/e 324.2 [(M+H)+, calcd for C18H22N5O 324.2].
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f27) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:14])=[N+:5]([O-:13])[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:2][C:3]1[C:4]([CH3:14])=[N+:5]([O-:13])[C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(CO)ccc(C(F)(F)F)[n+]1[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(CBr)ccc(C(F)(F)F)[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a stirring solution of 3-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (207 mg, 1.0 mmol) and carbon tetrabromide (400 mg, 1.2 mmol) in CH2Cl2 (5 mL) at 0° C. was added Ph3P (393 mg, 1.5 mmol) in small portions over 5 min. The reaction mixture was then stirred at 0° C. for 30 min. Analysis by HPLC/MS indicated the reaction was complete. The reaction mixture was directly loaded onto a silica gel cartridge (40 g) and eluted with a gradient of EtOAc (0-100%) in hexanes to afford 202 mg (75%) of the title compound as a white solid. HPLC/MS: retention time=2.10 min, [M+H]+=269.9.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[C:33]([F:36])([F:35])[F:34])[C:25]2=[O:37])[C:8]([NH:10][C:11]2[CH:16]=[N:15][C:14]([C@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([CH2:6][C@H:7]([N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[C:33]([F:35])([F:36])[F:34])[C:25]2=[O:37])[C:8]([NH:10][C:11]2[CH:16]=[N:15][C:14]([C@H:17]([OH:18])[CH2:21][OH:20])=[CH:13][N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@H](c2cnc(NC(=O)[C@H](CC3CCCC3)N3Cc4c(cccc4C(F)(F)F)C3=O)cn2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cnc([C@H](O)CO)cn1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A mixture of (S)-3-cyclopentyl-N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (74 mg, 0.14 mmol) in tetrahydrofuran (1.5 mL) was treated with a 1N aqueous hydrochloric acid solution (1.5 mL) and stirred at room temperature until there was no more starting material as indicated by TLC (overnight, ˜16 h). After this time, the reaction was treated with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3×20 mL). The organic layers were then combined and dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (4 g silica gel column, 100% ethyl acetate) to afford (S)-3-cyclopentyl-N-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (49 mg, 72%) as a white foam: [α]28D=−41.6° (c=0.25, methylene chloride); HR-ES(+) m/e calcd for C23H25N4O4F3 [M+H]+ 479.1901, observed 479.1899; 1H NMR (300 MHz, DMSO-d6) δ 11.27 (s, 1H), 9.16 (s, 1H), 8.45 (d, J=0.91 Hz, 1H), 8.02 (t, J=8.45 Hz, 2H), 7.70-7.82 (m, 1H), 5.55 (br. s., 1H), 5.22 (dd, J=5.13, 10.26 Hz, 1H), 5.05 (d, J=18.11 Hz, 1H), 4.90-4.50 (br. s., 1H), 4.75 (d, J=18.11 Hz, 1H), 4.62 (t, J=5.13 Hz, 1H), 3.61-3.72 (m, 1H), 3.49-3.60 (m, 1H), 1.03-2.21 (m, 11H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])O1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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.O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]2[C:3](=[C:4]([NH2:5])[N:22]=[C:21]3[C:20]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:6]=1
Reactant: COc1ccc(Br)c(C#N)c1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)c(N)nc1ccccc12
Yield: 68 %

Procedure:
2-Bromo-5-methoxybenzonitrile (1.32 g, 6.23 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.36 g, 6.23 mmol), bis(triphenylphosphine)palladiumdichloride (0.437 g, 0.623 mmol) and potassium phosphate monohydrate (4.30 g, 18.68 mmol) were added to toluene (30 mL) and water (3 mL). The reaction mixture was degassed with bubbled nitrogen gas for 30 minutes before being refluxed under nitrogen for 15 h. After cooling, the reaction mixture was filtered through Celite® and the organic layer was extracted with ethyl acetate. After removal of the solvents, the crude material was triturated with 40 mL of DCM followed by 50 mL of hexanes to give 8-methoxyphenanthridin-6-amine (0.95 g, 68%) as a light yellow solid. The product was confirmed by GC/MS and NMR.