Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C=C(C(C)C)C=1S(N=[N+]=[N-])(=O)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[N-:29]=[N+:30]=[N-:31].[H-].[K+].C(NC(C)C)(C)C.C([Li])CCC.[Si:46]([O:53][CH2:54][CH2:55][N:56]1[C:62]2[N:63]=[CH:64][CH:65]=[CH:66][C:61]=2[C:60]2[CH:67]=[CH:68][CH:69]=[CH:70][C:59]=2[CH2:58][C:57]1=[O:71])([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].C(O)(=O)C>O1CCCC1>[N:29]([CH:58]1[C:59]2[CH:70]=[CH:69][CH:68]=[CH:67][C:60]=2[C:61]2[CH:66]=[CH:65][CH:64]=[N:63][C:62]=2[N:56]([CH2:55][CH2:54][O:53][Si:46]([C:49]([CH3:51])([CH3:50])[CH3:52])([CH3:48])[CH3:47])[C:57]1=[O:71])=[N+:30]=[N-:31]
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)Cc2ccccc2-c2cccnc21
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(N=[N+]=[N-])c2ccccc2-c2cccnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Wash potassium hydride (approximately 2 scoops, 35 weight % in mineral oil) with hexanes and decant to remove oil, add tetrahydrofuran (60 mL) and cool to −78° C. Dry a solution of 2,4,6-tris(1-methylethyl)-benzenesulfonyl azide (37.6 g, 121.6 mmol) in tetrahydrofuran (60 mL) over sodium sulfate for 45 minutes. Decant azide solution into the potassium hydride suspension over 15 minutes. Remove cold bath and allow it to warm to ambient temperature for 45 minutes; set aside dry solution. Cool a solution of diisopropylamine (17.0 mL, 121.0 mmol) and tetrahydrofuran (50 mL) to −78° C., add n-butyl lithium (52.1 mL, 130.3 mmol) dropwise over 5 minutes. Remove cold bath and allow it to warm for 15 minutes then cool back to −78° C. Cannulate into a −78° C. solution of 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (34.3 g, 93.1 mmol) in tetrahydrofuran (400 mL) over 5-10 minutes. Stir for one hour at −78° C. then remove cold bath and allow it to warm for 15 minutes (to approximately −45° C.). Cool to −78° C. and add the dried 2,4,6-tris(1-methylethyl)-benzenesulfonyl azide solution via cannula over 5-10 minutes. Remove bath and allow to warm to −5 to 0° C. over 1 hour. Cool in ice/water bath and add acetic acid (26.7 mL, 465.3 mmol) dropwise over 13 minutes. Allow to warm to ambient temperature over 65 minutes and quench with saturated sodium bicarbonate solution (14 Dilute reaction with ethyl acetate (600 mL) and water (2 L), separate layers, back extract from aqueous with ethyl acetate (2×400 mL). Wash combined organics with saturated aqueous sodium bicarbonate solution (500 mL) and brine (500 mL), dry over sodium sulfate and concentrate. Purify the residue by flash chromatography, eluting with ethyl acetate:hexane (0:100 to 100:0) to give the title compound as an oil (39.8 g, 92.3 mmol, 99%). MS (m/z): 410 (M+1).
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.C(OC(=O)[CH2:16][CH2:17][C:18]1[N:26]([CH2:27][C:28](OC(C)(C)C)=[O:29])[C:25]2[CH:24]=[C:23]([Cl:35])[N:22]=[CH:21][C:20]=2[CH:19]=1)C.Cl>C1COCC1.[Cl-].[Na+].O>[Cl:35][C:23]1[N:22]=[CH:21][C:20]2[CH:19]=[C:18]3[N:26]([C:25]=2[CH:24]=1)[CH2:27][C:28](=[O:29])[CH2:16][CH2:17]3
Reactant: CCOC(=O)CCc1cc2cnc(Cl)cc2n1CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCc2cc3cnc(Cl)cc3n2C1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.25 ml of 1M KOtBu THF solution and 2 mL of THF was cooled at −10° C. A solution of 3-(1-tert-Butoxycarbonylmethyl-6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)-propionic acid ethyl ester (0.07 g) in 0.5 mL of THF was added over r min. After stirring for 15 min at −10° C., 0.3 ml of 1 N HCl and 3 mL brine were added. The mixture was extracted with 10 mL of EtOAc, and extract was dried over Na2SO4, filtered, concentrated. The residue was dissolved in 10 mL of toluene and 0.3 g of silica gel was added, and the mixture was heated to reflux for 3 h. After cooling, the reaction mixture was filtered and concentrated. The residue was used for next step without further purification. MS (ESI): 221.1 (M+1).
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1.[OH-].[Na+]>C(Cl)Cl.O>[I:1][C:5]1[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][C:8]([NH2:10])=[N:9][C:4]=1[CH3:3]
Reactant: CCCCCNc1cc(C)nc(N)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of iodine (11.92 g) in DCM (300 mL) was added to a stirred mixture of the product from step (i) (8.3 g) and sodium hydroxide (3.42 g) in water (200 mL). The reaction mixture was stirred at rt overnight. The organic layer was separated and washed with sodium metabisulfate solution, then brine. The combined organic layers were dried, and the solvent evaporated under reduced pressure. The product was purified by chromatography eluting with DCM:MeOH; 95:5 to give the subtitle compound 11 g.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2N=C[CH:12]=[CH:11][N:10]=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2].BrC1[S:37]C=CN=1>>[CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2[S:37][CH:12]=[CH:11][N:10]=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2]
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Reactant: Brc1nccs1
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromo-1,3-thiazole provided the title compound as an amporphous solid:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=3F)=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH-](CC)CC)C.[Li+].[Li]>O1CCOCC1.C1COCC1>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[O:18][C:35]4[C:30](=[CH:31][C:32]([F:37])=[CH:33][C:34]=4[F:36])[C:20]4[C:19]3=[C:28]3[C:23](=[CH:22][CH:21]=4)[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27]3)=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Agent: CC[BH-](CC)CC
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)cc(F)c1OC3c1ccc(OCCN2CCCCCC2)cc1
Reaction time: 1 h

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-methanone (2.63 g, 5.1 mmol) in 60 mL dioxane and add 10 mL of a 1.0 M solution of lithium triethylborohydride in THF. At the end of one hour, add another 10 mL of the lithium reagent mixture is added and gently warm the reaction. After a further one hour, add an additional 25 ml of lithium triethylborohydride and heat the reaction to reflux and hold for 8 hours. Cool the reaction and quench with water. Extract the water with methylene chloride, dry the organic layer with molecular sieves and concentrate. Purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH:7]=[CH:8]/[C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][C:14](=[O:17])[CH2:15]3)[CH2:11][C@H:10]2[OH:18])=[CH:4][C:3]2[CH:37]=[CH:38][CH:39]=[CH:40][C:2]1=2.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C>C1COCC1>[S:1]1[C:5]([C@H:6]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH:7]=[CH:8]/[C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][CH:14]([OH:17])[CH2:15]3)[CH2:11][C@H:10]2[OH:18])=[CH:4][C:3]2[CH:37]=[CH:38][CH:39]=[CH:40][C:2]1=2
Reactant: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@H](/C=C/[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1O)c1cc2ccccc2s1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(3aR,4R,5R,6aS)-4-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one (7a, limiting reagent) is dissolved in anhydrous THF (0.5 M) under a nitrogen atmosphere and cooled to −78° C. A solution consisting of DIBAL-H (1 M in toluene, 2 molar equivalents) is added to the reaction mixture dropwise and stirred for 3 hours. Ethyl acetate (20 mL) is added and the mixture is stirred for an additional 5 minutes. The mixture is then treated with 30% aqueous K, Na tartrate and stirred vigorously overnight. The layers are separated and the organic phase is filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 8a.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10](B4OC(C)(C)C(C)(C)O4)=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].OC(C(F)(F)F)=O.Br[C:38]1[C:39]([CH3:54])=[C:40]([N:44]2[CH:49]=[CH:48][N:47]3[CH:50]=[CH:51][N:52]=[C:46]3[C:45]2=[O:53])[CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(CCO)=CC=CC=1.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>[CH:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([N:44]5[CH:49]=[CH:48][N:47]6[CH:50]=[CH:51][N:52]=[C:46]6[C:45]5=[O:53])[C:39]=4[CH3:54])=[CH:11][CH:12]=[C:13]([C:18]([NH2:20])=[O:19])[C:14]=3[NH:15]2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(B3OC(C)(C)C(C)(C)O3)c12
Reactant: Cc1c(Br)cccc1-n1ccn2ccnc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(NC(C)C)ccc4c23)cccc1-n1ccn2ccnc2c1=O
Temperature: 90 °C

Procedure:
Step 2 A suspension of impure 7-(isopropylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (60 mg, 0.053 mmol), 7-(3-bromo-2-methylphenyl)imidazo[1,2-a]pyrazin-8(7H)-one TFA salt (Intermediate 11-1, 22.3 mg, 0.053 mmol), tetrakis(triphenylphosphine)palladium (3.1 mg, 0.003 mmol) and 2 M aqueous sodium carbonate (0.080 mL, 0.160 mmol) in toluene-ethanol (4:1, 1.3 mL) was heated under nitrogen at 90° C. overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was dried and concentrated to provide 7-(isopropylamino)-4-(2-methyl-3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)-yl)phenyl)-9H-carbazole-1-carboxamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83-10.99 (1H, m), 8.01 (1H, br. s.), 7.83 (1H, dd, J=4.5, 1.0 Hz), 7.68-7.77 (1H, m), 7.59-7.67 (1H, m), 7.38-7.50 (3H, m), 7.24-7.38 (2H, m), 7.08 (1H, dd, J=8.4, 5.9 Hz), 6.76-6.87 (1.55H, m), 6.73 (1H, dd, J=7.4, 1.9 Hz), 6.48 (0.45H, d, J=8.8 Hz), 6.13-6.29 (1H, m), 5.44 (1H, t, J=8.3 Hz), 3.40-3.55 (1H, m), 1.70 (3H, d, J=11.4 Hz), 1.09 (6H, td, J=5.8, 3.4 Hz). Mass spectrum m/z 491.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:21]([O:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[CH2:22][CH3:23])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:37][C@:38]1([C:43]([NH:45][S:46]([C:49]2([CH3:52])[CH2:51][CH2:50]2)(=[O:48])=[O:47])=[O:44])[CH2:40][C@H:39]1[CH:41]=[CH2:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:17][C@H:15]1[CH2:16][N:12]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C@@H:21]([O:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[CH2:22][CH3:23])[C@H:13]([C:18](=[O:20])[NH:37][C@:38]2([C:43](=[O:44])[NH:45][S:46]([C:49]3([CH3:52])[CH2:51][CH2:50]3)(=[O:48])=[O:47])[CH2:40][C@H:39]2[CH:41]=[CH2:42])[CH2:14]1
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,4R)-1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (½ of material from step 3, 600 mg, 1.45 mmol), (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide-trifluoroacetic acid salt (571 mg, 1.59 mmol), HATU (578 mg, 1.52 mmol) and CH2Cl2 (10 mL). To the mixture was added N,N-diisopropylethylamine (1.01 mL, 5.79 mmol). The mixture was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel and was thrice washed with aq. HCl (1M); then brine. The organic solution was dried over MgSO4; filtered; then concentrated in vacuo. The resulting residue was subjected to silica gel chromatography (hexanes:acetone, 94:6 to 60:40) to afford tert-butyl ((2S,3S)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-1-oxo-3-(pent-4-en-1-yloxy)pentan-2-yl)carbamate as a colorless solid foam (480 mg, 52%). MS: MS m/z 641.5 (M++1).
Reaction SMILES: COC1C=CC(N)=CC=1.C(N(CC)CC)C.[N+](C1C=C(S(Cl)(=O)=O)C=CC=1)([O-])=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38](C2C=CC(OC)=CC=2)[S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=2)(=[O:41])=[O:40])=[CH:34][CH:33]=1>ClCCl>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N+:48]([O-:50])=[O:49])[CH:43]=2)(=[O:41])=[O:40])=[CH:34][CH:33]=1
Reactant: COc1ccc(N(c2ccc(OC)cc2)S(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 8 h

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer. The flask was charged with p-anisidine (13.0 mmol) followed by dichloromethane (50 mL). Triethylamine (25.9 mmol) was added followed by 3-nitrobenzenesulfonyl chloride (16.2 mmol). Additional dichloromethane (75 mL) was added for solubility. The reaction was allowed to stir overnight. After 18 hours, TLC (dichloromethane/silica) indicated that the reaction was not complete. One additional equivalent of 3-nitrobenzenesulfonyl chloride (13.0 mmol), and two equivalents of triethylamine (25.9 mmol) were added to the reaction. After 10 minutes, TLC indicated that two products had formed and all starting anisidine was consumed. The reaction was washed with 2N HCl (100 mL), dried (Na2SO4), filtered, and the solvent removed under diminished pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g). The silica plug was eluted with dichloromethane (100 mL fractions) until the first product eluted from the filter column (TLC, dichloromethane/silica). The solvent system was changed to 9:1 dichloromethane/ethyl acetate and fractions were taken (100 mL) until the second product eluted from the filter column. The solvent from both samples was removed under reduced pressure to yield a mixture of the undesired N,N-bis-(4-methoxyphenyl)-3-nitrobenzenesulfonamide and the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[Li]CCCC.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[N:39]([CH2:52][CH:53]([CH3:55])[CH3:54])[S:40]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]2[CH2:51][O:50]2)=[CH:45][CH:44]=1)(=[O:42])=[O:41]>O1CCCC1>[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[N:39]([CH2:52][CH:53]([CH3:55])[CH3:54])[S:40]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:50])[CH2:51][CH2:1][C:2]2[N:3]=[N:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)=[CH:45][CH:44]=1)(=[O:42])=[O:41]
Reactant: Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)cc2)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CCc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 13.9 %

Procedure:
To a solution of 5-methyl-2-trityl-2H-tetrazole (68.5 mg, 0.21 mmol) in tetrahydrofuran (THF) (1 mL), stirred under nitrogen at −70° C., was added a solution of n-BuLi (1.6 M in hexanes, 0.144 mL, 0.231 mmol) in Tetrahydrofuran (THF) (1 mL) dropwise over 1 minute. The reaction mixture was then stirred at −78° C. for 45 minutes. N-(2,4-dimethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (108 mg, 0.300 mmol) in Tetrahydrofuran (THF) (1 mL) was added dropwise at −78° C. over 1 minute. The reaction mixture was then stirred at −78° C. for a further 1 hour and then allowed to warm to room temperature. The reaction was carefully quenched using a few drops of water, under nitrogen. Ethyl acetae (3 mL) and water (2 mL) were added and the reaction stirred vigorously for 5 minutes. The organic phase was separated using a hydrophilic frit and concentrated in vacuo to give a residue. LCMS analysis showed incomplete reaction, so the above reaction procedure repeated using fresh n-butyl lithium solution and reintroducing the crude residue instead of new starting material, this resulted in improved conversion. The residue was then purified by flash (Si) chromatography (using a 0-25% ethyl acetate-cyclohexane gradient) to give the required product (20 mg) as a colourless gum. LCMS RT 1.56 mins.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27]1[C:28]([CH3:42])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([CH3:42])=[C:27]([NH:26][CH2:24][CH3:25])[CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 87.1.1) to give the title compound as a white solid. (HPLC: tR 2.18 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.95-7.91 (m, 1H), 7.88-7.86 (m, 1H), 7.61-7.59 (m, 1H), 6.78-6.76 (m, 1H), 5.23 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.21-3.14 (m, 2H), 2.33 (s, 3H), 1.97 (s, 3H), 1.25 (t, 3H))
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:27])[CH:5]=[C:6]2[C:10]=1[C:9](=O)[CH:8]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[CH2:7]2.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].S(Cl)(Cl)=O>O1CCCC1.CO.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH3:27])[CH:5]=[C:6]2[C:10]=1[C:9]([C:29]([F:31])([F:30])[F:28])=[C:8]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:14][CH2:13]1)[CH2:7]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCCC1CCC(C2CCC(C3Cc4cc(C)cc(F)c4C3=O)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCCC1CCC(C2CCC(C3=C(C(F)(F)F)c4c(F)cc(C)cc4C3)CC2)CC1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
8.5 g (0.023 mol) of 7-fluoro-5-methyl-2-(4′-propylbicyclohexyl-4-yl)-indan-1-one are dissolved in 50 ml of-tetrahydrofuran and the solution is cooled down to 0° C. 3.7 ml (0.025 mol) of trifluoromethyltrimethylsilane are added. 0.1 ml of tetrabutylammonium fluoride (1 M solution in THF) are added. After the reaction has ended, the mixture is subjected to conventional workup, and then the product is taken up in 40 ml of methanol, 200 mg of potassium fluoride are added and the mixture is refluxed for 10 hours. The resulting carbinol is dissolved in 30 ml of pyridine and 1.7 ml (0.024 mol) of thionyl chloride are added dropwise. The mixture is stirred for 10 hours at room temperature and then subjected to conventional workup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12].[F:13][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.CC(=O)OCC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:10][F:13])=[CH2:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: F[B-](F)(F)F
Reactant: C=C(C)c1cc(Cl)c(Cl)c(Cl)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(CF)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 36.2 %

Procedure:
To a mixture of 1,2,3-trichloro-5-(prop-1-en-2-yl)benzene (660 mg, 3 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium bis(tetrafluoroborate) (1.115 g, 3.15 mmol) in DMF (25 ml). The mixture was stirred at 75° C. for 3 h. The mixture was washed with H2O and extracted with EA (30 ml×2). The mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (7:1 to 5:1) to give the desired product (260 mg, yield 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:33])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12
Reactant: Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(-c5ccncc5)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
10 mg (0.04 mmol) of {3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}amine (from example XLII) and 8.40 mg (0.04 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 1.5 ml of water. 5.6 μl of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline using saturated sodium carbonate solution and extracted three times with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.