Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)C(C)C)(C)C.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (130 mg, 0.5 mmol, 1 eq) and N,N-diisopropylethylamine (0.26 mL, 3 eq) in anhydrous dichloromethane (10 mL) at room temperature was added dropwise cyclopropane carbonyl chloride (0.26 mL, 3 eq). After the reaction mixture was stirred at ambient temperature for two hours, it was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (with 10% THF added). The organic layer was isolated, washed with brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the residue was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:30) to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide as a white powder in amount of 51 mg.
Reaction SMILES: [C:1]([N:8]1[C@@H:17](C(O)=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCN[C:24]1=[O:25].OS(O)(=O)=O.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.[CH3:120][C:121]([CH3:141])=[CH:122][CH2:123][CH2:124]/[C:125](/[CH3:140])=[CH:126]/[CH2:127][CH2:128]/[C:129](/[CH3:139])=[CH:130]/[CH2:131][S:132][CH2:133][C@H:134]([NH2:138])[C:135]([OH:137])=[O:136]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[C@@H:17]([C:24]([NH:138][C@@H:134]([CH2:133][S:132][CH2:131]/[CH:130]=[C:129](\[CH3:139])/[CH2:128][CH2:127]/[CH:126]=[C:125](\[CH3:140])/[CH2:124][CH2:123][CH:122]=[C:121]([CH3:141])[CH3:120])[C:135]([OH:137])=[O:136])=[O:25])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture and stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (250 mg, 48%) to yield Compound N-50. 1H-NMR (500 MHz, CD3OD): δ 1.33 (s, 9H), 1.61 (bs, 6H), 1.68 (bs, 6H), 1.69-1.73 (m, 2H), 1.99 (t, J=7.5 Hz, 2H), 2.06-2.17 (m, 8H), 2.73 (dd, J=7.5, 14.0, 1H), 2.87 (dd, J=5.0, 14.0 Hz, 1H), 3.16 (dd, J=7.5, 13.0 Hz, 1H), 3.25 (dd, J=8.0, 13.0 Hz, 1H), 3.25-3.30 (m, 2H), 3.73 (dd, J=5.5, 14.0 Hz, 1H), 4.55-4.61 (m, 2H), 5.12 (dd, J=8.0, 17.0 Hz, 2H), 5.20 (t, J=7.5 Hz, 1H), 7.39-7.88 (m, 3H), 8.20-8.24 (m, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.2, 16.3, 17.9, 26.0, 27.4, 27.8, 28.1, 28.7, 30.4, 30.5, 30.9, 33.4, 36.6, 37.9, 40.8, 40.9, 53.3, 56.9, 57.7, 121.5, 124.8, 125.1, 125.5, 126.5, 126.6, 127.3, 128.6, 128.7, 128.8, 129.3, 129.9, 132.1, 133.5, 134.7, 135.5, 136.3, 140.6, 157.5, 173.7, 174.2; ES-MS: mass calcd for Chemical Formula: C33H48N2O5S 584.8. Found (M+Na) m/z 607.4.
Reaction SMILES: [H][H].[C:3]([C:7]([C:10]([Cl:13])([F:12])[F:11])([Cl:9])[Cl:8])([F:6])([F:5])[F:4]>[Pd]>[C:3]([C:7]([C:10]([Cl:13])([F:11])[F:12])([Cl:9])[Cl:8])([F:6])([F:5])[F:4].[C:3]([CH:7]=[C:10]([F:12])[F:11])([F:6])([F:5])[F:4].[C:3]([C:7](=[C:10]([F:12])[F:11])[Cl:8])([F:6])([F:5])[F:4]
Reactant: [H][H]
Agent: [Pd]
Agent: FC(F)(F)C(Cl)(Cl)C(F)(F)Cl
Product: FC(F)=C(Cl)C(F)(F)F
Product: FC(F)=CC(F)(F)F
Reaction time: 12.6 h

Procedure:
The test procedure described in Example 2 was repeated except that the catalyst was 0.5% Pd on alumina, the reaction temperature was held to approximately 150° C. and the duration of the test was approximately 12.6 hours. The mole ratio of hydrogen to CF3CCl2CF2Cl introduced into the quartz reactor was approximately 1.09. The reaction product was collected and its composition was determined. The reaction resulted in a conversion of CF3CCl2CF2Cl of about 97.8%, with a selectivity for CF3CH═CF2 of 6.8%, for CF3CCl═CF2 of 85.4%, and for CF3CHClCF2Cl of 3.8%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]([OH:32])([C:30]#[CH:31])[CH3:29].C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:31]#[C:30][C:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)([OH:32])[CH3:29])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
A mixture of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (420 mg, 1.08 mmol), 2-(pyrimidin-2-yl)but-3-yn-2-ol (1 g, 6.75 mmol, 6.25 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg, 1.14 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred under nitrogen for 1 hr at 90° C. The resulting mixture was concentrated under vacuum and the residue was purified by preparative HPLC to yield 18 mg (4%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as a light brown solid: 1H NMR (400 MHz, D2O) delta 8.75 (d, J=5.2 Hz, 2H), 7.52 (d, J=5.6 Hz, 1H), 7.46 (t, J=5 Hz, 1H), 7.30 (s, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 6.24 (d, J=5.2 Hz, 1H), 3.90 (s, 2H), 3.61 (s, 2H), 1.80 (s, 3H); LC-MS: m/z=+418 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[CH3:19]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:23][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and glycine ethyl ester hydrochloride according to the procedure of Example 154 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J=7.1 Hz, 3H), 2.43 (t, J=6.1 Hz, 4H), 3.72 (t, J=6.1 Hz, 4H), 3.95 (d, J=5.8 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 7.04 (d, J=8.9 Hz, 2H), 7.77 (d, J=8.9 Hz, 2H), 8.63 (t, J=5.8 Hz, 1H); MS (ES) m/z: 305.2 (MH+); HRMS Calcd. for C18H22N2O4 (M+): 304.1423. Found: 304.1422.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: BrBr
Reactant: Cc1cnc(N)cn1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cnc(N)c(Br)n1
Yield: 56.4 %

Procedure:
To a suspension of 5-methylpyrazin-2-amine (1.09 g, 10 mmol) in chloroform (100 mL) was added pyridine (0.85 mL, 10.5 mmol). The mixture was stirred in a foil-wrapped flask fitted with an addition funnel, and a solution of bromine (0.54 mL, 10.5 mmol) in chloroform (10 mL) was added dropwise over 10 min. The mixture was allowed to react an additional 20 minutes after addition was complete and then poured into a separatory funnel containing 10 mL water. The phases were separated and the organics washed again with water, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting red oil was purified by silica gel chromatography with 12-100% EtOAc/hexanes. The major UV active peak was collected to give 3-bromo-5-methylpyrazin-2-amine (1.06 g, 5.64 mmol, 56.4% yield) as a cream-colored solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.85 (s, 1H) 6.42 (br. s., 2H) 2.25 (s, 3H). MS (LC/MS) R.T.=0.93; [M+H]+=189.9.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[CH:6]=2)[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([NH2:35])[CH3:34])[CH:30]=[CH:31][CH:32]=1>CN1C(=O)CCC1>[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:33]([NH:35][C:7]2[CH:6]=[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=2)[CH3:34])[CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: C[C@H](N)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1)c1cccc(Cl)c1
Temperature: 120 °C

Procedure:
To (Z)-5-((7-(cyclopropylamino)-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione (step c) (10 mg, 0.0275 mmol) in 200 uL NMP, was added (S)-1-(3-chlorophenyl)ethanamine (23.2 ul, 0.165 mmols) and the reaction mixture was heated in the microwave at 120° C. for 20 minutes. The mixture was concentrated and diluted with MeOH and purified by preparative HPLC to yield (S,Z)-5-((5-(1-(3-chlorophenyl)ethylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione LCMS (M+1=438)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13](C(Br)Br)[C:12]([Cl:18])=[CH:11][C:6]=1C(OC)=O)(=O)[CH3:2].[C:19](=[O:22])([O-])[O-:20].[Ca+2].[C:24](=[O:27])([O-])[O-].[Cs+].[Cs+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1.O.C(OCC)(=O)C>[Cl:18][C:12]1[C:13]([CH:24]=[O:27])=[CH:14][C:5]([O:4][CH2:1][C:2]2[CH:13]=[CH:14][CH:5]=[CH:6][CH:11]=2)=[C:6]([CH:11]=1)[C:19]([O:20][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:22]
Reactant: COC(=O)c1cc(Cl)c(C(Br)Br)cc1OC(C)=O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [Ca+2]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Cl
Temperature: 150 °C

Procedure:
A mixture of methyl 2-(acetyloxy)-5-chloro-4-(dibromomethyl)benzoate (may be prepared as described in Description 61; 2.1 g, 5.24 mmol) and calcium carbonate (1.05 g, 10.49 mmol) in 1,4-dioxane (5 ml)/water (5 ml) was heated at 150° C. for 6 hours. The solvent was removed in vacuo and the residue was suspended in N,N-dimethylformamide (5 ml). Cesium carbonate (3.76 g, 11.54 mmol) and benzyl bromide (0.94 ml, 7.87 mmol) were added. The mixture was heated at 50° C. for 18 hours. The N,N-dimethylformamide was removed and the residue was partitioned between 2M HCl (20 ml) and ethyl acetate (15 ml). The organic layer was separated and dried (MgSO4) and the solvent removed in vacuo. The residue was redissolved in N,N-dimethylformamide (5 ml) and cesium carbonate (3.76 g, 11.54 mmol) and benzyl bromide (0.94 ml, 7.87 mmol) were added. The mixture was heated for 2 hours at 50° C. and cooled, then ethyl acetate (15 ml) and water (10 ml) were added. The organic layer was washed with water (2×15 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (6:1 cyclohexane/ethyl acetate) gave the title compound as an off white solid. 1.4 g.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([OH:31])=O.[CH2:50]([NH2:58])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([NH:58][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:31]
Reactant: NCCc1ccccc1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCCc1ccccc1
Yield: 7 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with phenethylamine, the title compound was obtained as a white powder in 7% yield: mp 184-185° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32-7.17 (m, 9H), 5.62 (br s, 1H), 4.47 (s, 2H), 4.09-4.03 (m, 2H), 3.67-3.60 (m, 2H), 3.47-3.42 (m, 2H), 2.88 (d, J=6.9 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.2, 155.4, 152.3, 148.9, 138.7, 134.4, 129.7, 128.8, 128.7, 126.6, 122.1, 121.4, 118.0, 47.3, 42.0, 41.8, 41.1, 35.7, 17.1; MS (ES+) m/z 505.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Reactant: CC(C)C(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 15.4 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.22 mmol) and DIEA (0.11 mL, 0.66 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Isobutyryl chloride (0.03 mL, 0.26 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 72 (14 mg, 15% yield) as a white fluffy solid. LC-MS (M+H=413, obsd.=413).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[CH2:13][N:12]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])[C:9]2=[CH:10][CH:11]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:47][C:48]([S-:50])=[O:49].[K+]>O1CCCC1.O>[C:48]([S:50][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15]3)[CH2:13][N:12]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])=[O:27])[C:9]2=[CH:10][CH:11]=1)(=[O:49])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CCCCO)cc12
Reactant: CC(=O)[S-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)SCCCCc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(4-hydroxybutyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (120.7 mg, 0.246 mmol) was dissolved in tetrahydrofuran (2.5 mL). Thereafter, triethylamine (46 μL, 0.32 mmol) and methanesulfonyl chloride (21 μL, 0.27 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, insoluble matters were filtered, and the filtrate was then concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (2.4 mL), and S-potassium thioacetate (62 mg, 0.54 mmol) was then added to the above solution. The thus obtained mixture was stirred at room temperature for 15 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with water and brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(4-(acetylthio)butyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (89.2 mg, 66%) in the form of a brown oily product.
Reaction SMILES: [C:1](#N)[C:2]([CH3:4])=[CH2:3].C1(CC(O)(C)C#N)[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>CO.O>[OH:21][C:11]1[CH:12]=[C:13]2[C:3]3[C:17](=[CH:16][CH:15]=[CH:14]2)[C:18](=[O:20])[C:19]2[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:2]=3[CH:1]=1
Reactant: C=C(C)C#N
Reactant: CC(O)(C#N)Cc1cccc2c1C(=O)c1ccccc1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2-c2cc(O)cc3cccc1c23

Procedure:
There was obtained a distillate containing 35.7 g of methacrylonitrile, besides methanol and water. The distillation residue was then mushed or slurried with water, filtered, washed with water to neutrality, and finally well squeezed. The solid product thus obtained, consisting of 3-(1-anthraquinonyl)-2-hydroxy-2-methylpropionitrile: ##STR9## is suspended, still humid, in a solution of 500 cc of methanol containing 25 g of potassium hydroxide. This suspension was then reflux-heated for 1.5 hours and the red tinged solution thus obtained was freed of the insoluble impurities by filtering. It was then diluted with water up to 1.5 liters and then acidified with concentrated hydrochloric acid. Thereby was formed a yellow tinged precipitate which was filtered, washed with water to neutrality, and finally dried at 100° C. under vacuum until attaining a constant weight. In this way there were obtained 44.8 g of 2-hydroxybenzanthrone in the form of a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9].Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:36]=[C:35]([CH:37]3[CH2:39][CH2:38]3)[NH:34][N:33]=2)[CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:37]1([C:35]2[NH:34][N:33]=[C:32]([NH:31][C:29]3[CH:28]=[CH:27][N:26]=[C:25]([NH:10][CH:8]([C:7]4[N:6]=[C:5]5[CH:11]=[CH:12][N:13]([S:14]([C:17]6[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=6)(=[O:16])=[O:15])[C:4]5=[CH:3][C:2]=4[F:1])[CH3:9])[N:30]=3)[CH:36]=2)[CH2:39][CH2:38]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N)c(F)cc32)cc1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)c(F)cc32)cc1
Temperature: 135 °C
Yield: 22.5 %

Procedure:
A mixture of 1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (500 mg, 1.5 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (353 mg, 1.5 mmol), and DIPEA (581 mg, 4.5 mmol) in 2,4-dimethylpentan-3-ol (2 mL) was heated at 135° C. for 15 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford 180 mg (21%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4-diamine as a white solid. MS (ESI): m/z=533.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([CH2:9][OH:10])[NH:7]1)=[O:5])[CH3:2].[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH2:9][O:10][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16])[NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1N[C@@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1NC1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In a flame dried flask equipped with a magnetic stirring rod and a rubber septum with a N2 inlet was added (S,S) 3-hydroxymethylaziridine-2-carboxylic acid ethyl ester (296 mg, 2.04 mmol) and 12 ml of CH2Cl2. The reaction vessel was cooled to 0° C. then TBDMSCl (377 mg, 2.50 mmol) and DMAP (623 mg, 5.1 mmol) was added. The reaction was allowed to stir for 1 hour at 0° C. then at room temperature until the reaction was completed according to TLC (Rf=0.65; 7:3 hexanes/EtOAc). The reaction was diluted with CH2Cl2 then water was added. The organic layer was extracted three times, and the combined organic layers were washed first with saturated NaHCO3, then water, then brine and dried over solid Na2SO4. The mixture was filtered and dried under reduced pressure to afford a pale yellow oil, which was subjected to flash column chromatography (silica gel; 8:2 hexanes/EtOAc) to afford the title compound as a thick colourless oil in 99% yield. 1H NMR (CDCl3, 400 MHz) δ: 4.21 (q, J=3.6 Hz, 2H), 3.66 (dd, J=11.2 Hz, 5.2 Hz, 1H), 3.56 (dd, 10.8 Hz, 4.8 Hz, 1H), 2.42 (m, 2H), 1.37 (bt, 1H), 1.29 (t, J=7.2 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 172.6, 64.8, 61.7, 40.3, 33.7, 26.1, 18.5, 14.4, −5.1 ppm. HRMS (ESI) [M+H]+ calcd. for C12H25NO3Si 260.1676, found 260.1675.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[C:28]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]([O:36][CH2:37][CH3:38])=[O:35])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CO)cc3C)cc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)C(=O)OCC
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)methanol (from Example 65/Step 1) (0.2 M) and diethyl malonate (2 eq) in dry toluene was added tributylphosphine (2 eq) and N1,N1,N2,N2-tetramethyldiazene-1,2-dicarboxamide (2 eq). The reaction mixture was stirred at 120° C. overnight. Upon completion of the reaction, the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 50-100% EtOAc in hexanes) to afford diethyl 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzyl)malonate as a white solid.