Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:34]([OH:36])=[O:35])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(OCC=C)=O)=[CH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>ClCCl.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>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@@H:19]([C:34]([OH:36])=[O:35])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])=[CH:26][CH:25]=1
Reactant: C=CCOC(=O)Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A 500 mL cylindrical glass vessel equipped with a coarse glass frit was charged with 10 g of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-[[(2-propenyloxy)carbonyl]amino]-L-phenylalanine substituted Wang resin (10 g) obtained from Example 35 and a solution prepared from Pd(Ph3P)2Cl2 (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mmol) in dry dichloromethane (150 mL). The resulting mixture was agitated for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 mL, 74.3 mmol). The resulting mixture was agitated for 1 hour. To the mixture was added tri-n-butyl tin hydride (10 mL, 37 mmol). Agitation was continued for 1 hour and the mixture was filtered. To the resulting resin was added a solution prepared from Pd(Ph3P)2Cl2 (1.6 g, 2.3 mmol) and acetic acid (5 mL, 83 mmol) in dried dichloromethane (150 mL). The mixture was agitated for 30 minutes followed by the addition of tri-n-butyl tin hydride (20 mL, 74.3 mmol). The resulting mixture was agitated 1 hour. To the mixture was added additional tri-n-butyl tin hydride (10 mL, 37.15 mmol). Agitation continued for 1 hour. After the second deprotection cycle, the mixture was washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL) to give 4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin suitable for use in subsequent steps.
Reaction SMILES: [BH4-].[Na+].[CH:3]12[CH2:9][CH:6]([CH:7]=[CH:8]1)[CH2:5][CH:4]2[CH:10]=[O:11].Cl>C(O)C>[CH:3]12[CH2:9][CH:6]([CH:7]=[CH:8]1)[CH2:5][CH:4]2[CH2:10][OH:11]
Reactant: O=CC1CC2C=CC1C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium borohydride (15.49 g, 0.409 mol) in absolute ethanol (350 ml) was added dropmise to a stirred solution of bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (50.0 g, 0.409 mol) in absolute ethanol (300 ml) at 50°-60°. Following the addition, the reaction mixture was stirred at ambient temperature for 4 h. The solution was then acidified to congo red with dilute hydrochloric acid (2 M), filtered, and this solution was reduced to low volume under reduced pressure. Water (200 ml) was then added, and the mixture was stirred, when a white solid seperated. The reaction mixture was filtered, and the agueous solution was then extracted with ether (3×150 ml). The ether extracts were combined and dried (MgSO4), and the solution was then concentrated under reduced pressure to afford a pale yellow oil. Distillation of the oil gave bicyclo[2.2.1]hept-5-ene-2-methanol, b.p. 98°-100°/15 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:23]([NH:25][NH:26][CH:27]=O)=O>ClCCl>[N:25]1[N:26]=[CH:27][N:1]([C:2]2[CH:22]=[CH:21][C:5]([CH2:6][C:7]3[NH:8][C:9](=[O:20])[C:10]4[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=4[N:12]=3)=[CH:4][CH:3]=2)[CH:23]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Reactant: O=CNNC=O
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(-n4cnnc4)cc3)nc12
Temperature: 200 °C
Reaction time: 0.92 h
Yield: 34.3 %

Procedure:
A mixture of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (297 mg, 0.0010 mol) and 1,2-diformylhydrazine (101 mg, 0.00115 mol) was heated to 200° C. The resulting melt was then stirred under a nitrogen atmosphere at this temperature for 55 minutes. On cooling, the solid was dissolved in dichloromethane:methanol, pre-absorbed onto silica and purified by flash column chromatography eluting with a solvent gradient of dichloromethane:methanol (99:1 to 96:4 by volume) then dichloromethane:methanol:0.880 aqueous ammonia (90:10:1 by volume). Crystallisation from ethyl acetate/methanol gave the title compound (120 mg), m.p.297-300° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([CH2:23][C:24](=[O:26])[NH2:25])[C:16]([Cl:22])=[CH:17][CH:18]=2)[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:3])[CH3:2].C[O:29][C:30](=O)[C:31]([C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH3:42])[CH:34]=1)=O.CC([O-])(C)C.[K+].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:23]3[C:24](=[O:26])[NH:25][C:30](=[O:29])[C:31]=3[C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH3:42])[CH:34]=3)[C:16]([Cl:22])=[CH:17][CH:18]=2)[CH:13]=1)[CH2:8][CH2:9][F:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCF)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C2=C(c3c(Cl)ccc4ccc(CN(CCF)C(=O)OC(C)(C)C)cc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.17 h

Procedure:
(8-Carbamoylmethyl-7-chloro-naphthalen-2-ylmethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (80 mg, 0.20 mmol) and (1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (57 mg, 0.26 mmol) are dissolved under an atmosphere of argon in dry THF (4 ml). Activated molecular sieves 3 Å (100 mg) is added. After 10 minutes at RT, a solution of 1.0 M KOtBu in THF (0.61 ml, 0.61 mmol) is added in one portion. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. The residue is directly used in the next reaction. ES+-MS: 579.2, 580.5 [M+H+H2O]+. ES−-MS: 560.2, 561.5 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:31]4[C:30](=[O:32])[CH2:29][CH2:28][CH:27]4[CH3:26])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C#N)CC2)c(C)c1
Yield: 92.3 %

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1 g) described in Preparation Example 187 and 5-methylpyrrolidin-2-one (372 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (965 mg) was obtained.
Reaction SMILES: [K].[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1.[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[F:2][C:3]([F:20])([F:21])[C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH2:22][CH2:23][CH2:24][CH3:25])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCCBr
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1

Procedure:
In anhydrous dimethyl formamide was dissolved 3.2 g. of potassium salt of N-(3-trifluoromethylphenyl)anthranilic acid. To the solution was added 5.0 g. of n-butyl bromide. The mixture was heated at 100°-120° C. for 5 hrs. while stirring. The precipitated potassium bromide was taken out by filtration. The filtrate was concentrated and the residue obtained was distilled to obtain 3.1 g. of light yellow liquid having a boiling point of 190°-192° C. (5 mmHg).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]=1[C:10](Cl)=[O:11])[CH2:2][CH2:3][CH3:4].Br.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]=1[C:10]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)Cl
Reactant: Nc1ccc(-c2ccc(O)cc2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.9 %

Procedure:
2-Butyl-benzofuran-3-carbonyl chloride (2.22 g, 9.36 mmol), prepared in step 2 of Example 4, in 40 mL of anhydrous THF was added under nitrogen dropwise over 20 minutes to a mixture of the HBr salt of 4′-amino-biphenyl-4-ol (3.26 g, 12.3 mmol), prepared in the previous step, and triethylamine (3.42 mL, 24.5 mmol) in 100 mL of anhydrous THF at ice bath temperature. After the addition the reaction was stirred at room temperature for 20 h. The reaction was filtered and the filtrate concentrated under reduced pressure to give a solid. Purification of the solid on 1 Kg of silica gel (230-400 mesh) using 30% ethyl acetate-hexane as the eluent gave 2-butyl-N-(4′-hydroxy[1,1′-biphenyl]-4-yl)-1-benzofuran-3-carboxamide (2.27 g, 48%) as an off-white solid, mp 181-183° C.; MS (APCI) m/z 386 [M+H]+. Elemental Analysis for C25H23NO3: Calc'd: C, 77.90; H, 6.01; N, 3.63; Found: C, 77.48; H, 5.86; N, 3.56.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@@:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.[O:59]=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH3:1][CH2:2][C@@:3]12[O:59][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: O=O
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
100 mg. of 3',4'-anhydro-vinblastine are oxidized with oxygen from the air in an analogeous manner to that set forth in the Example 16, with the only difference that the reaction is performed in the presence of 4 mg. of 2,2'-azo-bis-isobutyronitrile.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:24][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([N:14]3[CH2:15][CH2:16][CH2:17][C@@H:13]3[CH3:12])[N:23]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: C[C@H]1CCCN1c1cccc(N)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (300 mg, 1.3 mmol), (S)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (252 mg, 1.42 mmol), Pd2(dba)3 (75 mg, 0.13 mmol), BINAP (324 mg, 0.52 mmol), Cs2CO3 (1272 mg, 3.9 mmol) and dioxane (20 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (124 mg, 29%) as a yellow solid. LC-MS: [M+H]+, 329.0, tR=1.951 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH2:17]([O:20][C:21](Cl)=[O:22])[CH2:18][CH3:19]>>[CH2:17]([O:20][C:21]([N:10]1[C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=2[CH:8]=[C:9]1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:22])[CH2:18][CH3:19]
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: CCCOC(=O)Cl
Product: CCCOC(=O)n1c(-c2cnn(C)c2)cc2cnc(Br)cc21

Procedure:
Prepared according to Preparation 128 using 6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22) and propylchloroformate. 1H-NMR (500 MHz, CDCl3): δ 0.96 (t, J=7.4 Hz, 3H), 1.38 (m, 2H), 3.97 (s, 3H), 4.36 (t, J=6.7 Hz, 2H), 6.59 (s, 1H), 7.62 (s, 1H), 7.65 (s, 1H), 8.17 (s. 1H), 8.56 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:22])[C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[CH3:23]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[C:8]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC1(CC)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 3 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 10-chloro-2-cyclopentyl-4,4-diethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 251; 2.5 g, 7.76 mmol) in DMA (50 mL) under nitrogen was added methyl iodide (0.627 mL, 10.0 mmol). The mixture was cooled on an ice/water bath to 3° C., and sodium hydride (60% mineral oil dispersion; 0.567 g, 11.8 mmol) added in one portion. The reaction mixture was stirred on the ice/water bath for 1 hour before warming to room temperature and the reaction stirred for 4 hours. The reaction mixture was evaporated to dryness to afford a black solid, which was quenched with saturated aqueous NH4Cl solution (50 mL), extracted with DCM (3×100 mL), dried and solvent removed in vacuo to yield a black solid which was purified on a silica column eluting with DCM. The obtained solid was added to a diethyl ether and sonicated and the resultant material filtered and dried to yield the title compound as an off white solid (2.1 g, 80%).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]#[N:17])[C:10]([C:18]#[N:19])=[CH:9]2)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[Na].[NH3:24]>CO>[CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2=[CH:12][C:11]3[C:16](=[NH:24])[NH:17][C:18](=[NH:19])[C:10]=3[CH:9]=[C:8]2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCSc1ccc2cc(C#N)c(C#N)cc2c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCSc1ccc2cc3c(cc2c1)C(=N)NC3=N

Procedure:
In an atmosphere of nitrogen, 30.0 g (0.11 mole) of 6-n-butylthio-2,3-dicyanonaphthalene was added to a solution of sodium methoxide in methanol prepared by adding 1.46 g (64 mmoles) of metallic sodium in 5 portions to 350 ml of anhydrous methanol. While thoroughly stirring the mixture, anhydrous ammonia gas was slowly bubbled at room temperature over a period of about one hour. Then, the mixture was refluxed for about 3 hours, while bubbling anhydrous ammonia gas. After cooling, the yellow solid precipitated was filtered and the residue was thoroughly washed with methanol and dried under reduced pressure to obtain 30 g of 6-n-butylthio-1,3-diiminobenz[f]isoindoline as a yellow solid. FIG. 6 illustrates its IR spectrum. Without further purification, it was used in the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[NH2:1][C:2]1([C:14]([O:16][CH3:21])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1
Reactant: COC1(C(F)(F)F)CCC(N)(C(=O)O)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1

Procedure:
12.20 g (corresponds to about 37.58 mmol) of 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylic acid (Example 18A) were suspended in 210 ml of methanol, and 10.4 ml (142.80 mmol) of thionyl chloride were added at 0° C. The mixture was boiled under reflux for 2 hours and cooled, another 10.4 ml (142.80 mmol) of thionyl chloride were added at 0° C. and the mixture was boiled under reflux for a further 2 hours. The reaction was cooled, another 10.4 ml (142.80 mmol) of thionyl chloride were added and the mixture was heated at reflux overnight until the reaction had gone to completion. For work-up, about 100 ml of methanol were distilled off and the concentrate was poured into 1 l of saturated aqueous sodium carbonate solution. The product was extracted with ethyl acetate and the organic phase was dried over sodium sulphate. Concentration by evaporation gave 7.01 g (73% of theory) of the title compound as a yellowish oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:5]=1[F:27].Cl>C1COCC1.O>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:8]3[CH:7]=[CH:6][C:5]([F:27])=[C:4]([CH:9]=3)[C:3]([OH:28])=[O:2])=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(F)c(C(=O)OC)c2)c1C#Cc1ccc(N)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(-c2ccc(F)c(C(=O)O)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 1.5 g (3.98 mmol) 5-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 334 mg (7.97 mmol) LiOH in 20 mL THF and 5 mL water. The reaction mixture is stirred over night at 50° C. Aqueous 1 M HCl is added until pH 5 is reached. The solvent is removed under reduced pressure and the residue is stirred in MeOH. After drying the crude product (0.8 g) is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1Br.C1(C)C=CC=CC=1.C(O)C>C(OCC)C.O.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>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: Brc1ccccc1Br
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ccccc2Br)c1
Temperature: 90 °C
Yield: 69.3 %

Procedure:
A mixture of 3-cyanophenylboronic acid (735 mg, 5 mmol), 1,2-dibromobenzene (2.36 g, 10 mmol) potassium carbonate (6.9 g, 50 mmol) and tetrakis(triphenylphosphine)palladium(0) (580 mg, 0.5 mmol) in 1:1 toluene/ethanol (40 ml) was stirred and heated at 90° C. under nitrogen for 3 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography using Biotage with ethyl acetate/iso-hexane (1:19) to yield the title compound as a white solid (895 mg 69%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.C([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=O)C>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[OH:29])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccccc2O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (180 mg, 0.74 mmol) and triethylamine (150 μL, 1.1 mmol) in methylene chloride (20 mL) was added dropwise acetylsalicyloyl chloride (160 mg, 0.78 mmol) in methylene chloride (10 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in 99.5% ethanol (25 mL) and concentrated hydrochloric acid (3 mL) was added. After 17 h, the pH was adjusted to 8 and the solvent was evaporated in vacuo. The residue was partitioned between water and methylene chloride. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 170 mg (63%) of the title compound as white crystals: mp 87° C. decomp; [α]21D -18° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 365 (33, M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH3:16])[C:11](=[O:13])[CH3:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1NC(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)cc1N(C)C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To N-(5-bromo-2-methoxy-pyridin-3-yl)-acetamide (Stage 62.1.3, 100 mg, 0.408 mmol) DMF (1 ml) was added NaH 55% in oil (19.6 mg, 0.45 mmol). The reaction mixture was stirred for 10 min at rt then was added MeI (0.031 ml, 0.49 mmol). The reaction mixture was stirred for 1 h at rt then quenched with brine and extracted with EtOAc (2×). The organic layers are washed with brine (3×), dried over Na2SO4, filtered and evaporated. The crude product was purified by Prep.HPLC. The fractions containing the product were collected together and basified with NaHCO3, before being concentrated and extracted with EtOAc (3×). The organic layers were dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an off-white solid (HPLC: tR 2.75 min (Method A); M+H=259, 261 MS-ES).