Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-])=O)[CH:3]=1.Cl[Sn]Cl>Cl.CCO>[NH2:22][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 59.1 %

Procedure:
In a similar fashion using route 1 general procedure 4, 4-chloro-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 263) (280 mg, 0.77 mmol), SnCl2 (383 mg, 3.08 mmol), 6N HCl (2 drops) and EtOH (4 ml) for 6 h at 85° C. gave the title compound (152 mg, 59%) after purification by column chromatography with DCM/MeOH (97:3) as the eluent.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:19][CH:20]4[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: OC1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 30.7 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (300 mg, 1.14 mmol) and trans-4-aminocyclohexanol hydrogenchloride (327 mg, 2.84 mmol) in NMP (2.0 mL) was added NaHCO3 (286 mg, 3.41 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (120 mg, 0.350 mmol, 31%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]1([C:13]#[N:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][C:31](Cl)=[O:32])=[C:25]([CH3:34])[CH:24]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH3:34])[C:26]([CH2:30][C:31]([N:4]([C:5]2([C:13]#[N:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]2)[O:3][CH2:1][CH3:2])=[O:32])=[C:27]([CH3:29])[CH:28]=1
Reactant: Cc1cc(Cl)cc(C)c1CC(=O)Cl
Reactant: CCONC1(C#N)CCN(OC)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCON(C(=O)Cc1c(C)cc(Cl)cc1C)C1(C#N)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-ethoxyamino-1-methoxy-piperidine-4-carbonitrile (2.0 g, 10.04 mmol), triethylamine (3.49 ml, 2.54 g, 25.09 mmol) and a catalytic amount of 4-dimethylamino-pyridine in tetrahydrofuran (10 ml) at 0° C. was added a solution of (4-chloro-2,6-dimethyl-phenyl)-acetyl chloride (2.18 g, 10.04 mmol) in tetrahydrofuran (1 ml) dropwise. The suspension was stirred at 0° C. for 15 minutes, and at room temperature overnight. The reaction mixture was evaporated, diluted with ethyl acetate and water, and the layers separated. The aqueous phase was extracted with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The crude material was triturated with diisopropyl ether, filtered and the filtrate concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:1). Yield: 1.53 g of 2-(4-chloro-2,6-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-ethoxy-acetamide (title compound P3ii.49) as a colorless oil, which solidified upon standing, mp 100-103° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([OH:20])(=[O:19])[CH3:18].C([O:24][C:25](=[O:27])C)(=O)C.P(=O)(O)(O)O>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:3]2[CH2:11][CH2:12][C:18]([C:25]([OH:24])=[O:27])([C:17]([OH:20])=[O:19])[CH2:5][CH:4]=2)=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(-c2ccccc2)cc2ccccc21
Agent: O=P(O)(O)O
Solvent: O
Product: Cn1c(-c2ccccc2)c(C2=CCC(C(=O)O)(C(=O)O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
A mixture of 9.0 g (0.043 mol) of 1-methyl-2-phenylindole, 9.3 g (0.05 mol) 4,4-cyclohexanonedicarboxylic acid, 100 mL of acetic acid, 4.7 mL of acetic anhydride, and 1 mL of 85% phosphoric acid was stirred at room temperature for 17 h, and then 100 mL of water was added dropwise to give a white solid which was collected and washed with water. The solid was taken up in ether, washed with water three times and with brine two times, dried over magnesium sulfate, concentrated in vacuo, and crystallized from acetonitrile to give 8.4 g (52%) of 4-(1methyl-2-phenyl-1H-indol-3-yl)-3-cyclohexene-1,1-dicarboxylic acid, m.p. 210°-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([NH:17][NH2:18])=[O:16])=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26](Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:25]([C:26]1[O:16][C:15]([CH2:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:17][N:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NN
Reactant: O=C(Cl)Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(Cc2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 8, Step 6, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid hydrazide and phenylacetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:17](I)[CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH3:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(OCC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with ethyl iodide (0.5 mL), K2CO3 (200 mg) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent under vacuum gave the crude product, which was purified by column chromatography to give 175 mg (77% yield) of 4-ethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as white solid.
Reaction SMILES: COC([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](OCC3C=CC=CC=3)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[CH3:25][O:26][C:27](=[O:36])[CH2:28]C1C=CC=C(Br)C=1.[CH2:37]([O:44]C1C=C(B(O)O)C=CC=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[Ba+2].[OH-]>COCCOC.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.O>[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:13]1([O:44][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:14]=[CH:15][CH:16]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=2)[CH2:12]1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)c1cccc(-c2cccc(OCc3ccccc3)c2)c1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CC1(OCc2ccccc2)C=CC=C(c2ccccc2)C1
Yield: 49 %

Procedure:
2-(3-Benzyloxy-biphenyl-3-yl)-acetic acid methyl ester (32) was synthesized following the procedure described for the preparation of 29 using 3-bromo-phenyl acetic acid methyl ester (31) (0.31 g, 1.35 mmol), 3-benzyloxy-phenyl boronic acid (0.45 g, 2 mmol), barium hydroxide (0.5 g, 3 mmol) and Pd(PPh3)4 (0.15 g, 0.13 mmol), in DME (10 mL)/water (4 mL). Purification by flash column chromatography on silica gel gave pure compound 32 (0.22 g, 49% yield) as a white solid (m p 50-52° C.).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].O[NH:38][C:39]([C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH2:50][OH:51])=[CH:44]2)=[NH:40]>CN(C=O)C.CCOC(C)=O>[OH:51][CH2:50][C:45]1[NH:46][C:47]2[C:43]([CH:44]=1)=[CH:42][C:41]([C:39]1[N:40]=[C:27]([C:26]3[CH:30]=[CH:31][C:32]([O:33][CH:34]([CH3:36])[CH3:35])=[C:24]([CH:25]=3)[C:22]#[N:23])[O:29][N:38]=1)=[CH:49][CH:48]=2
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1ccc2[nH]c(CO)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CO)cc4c3)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described on WO2005/58848, 144 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 15 min. N-Hydroxy-2-(hydroxymethyl)-1H-indole-5-carboximidamide (D25) (144 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 4 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from EtOAc/ether to afford 5-{3-[2-(hydroxymethyl)-1H-indol-5-yl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile (E12) (70 mg) as a light brown solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 4.65 (2H, d), 4.99 (1H, m), 5.36 (1H, t), 6.46 (1H, s), 7.49 (1H, d), 7.56 (1H, d), 7.79 (1H, dd), 8.28 (1H, dd), 8.42 (1H, d), 8.52 (1H, d), 11.43 (1H, s). MS (ES): C21H18N4O3 requires 374; found 375.0 (M+H+).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[C@H:5]([N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>CO.O=[Pt]=O.[Pt]>[NH2:2][CH2:1][CH2:3][CH2:4][C@H:5]([N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:26])([F:27])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CN([C@@H](/C=C/C#N)Cc1ccccc1)S(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=[Pt]=O
Agent: [Pt]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN([C@@H](CCCN)Cc1ccccc1)S(=O)(=O)c1ccccc1OC(F)(F)F
Reaction time: 12 h

Procedure:
To a solution of compound 31h (3.7 g, 7.7 mmol) in MeOH (200 mL) were added PtO2 (0.1 g), Pt/C (0.3 g) and TFA (1.9 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 12 h. The mixture was filtered and concentrated. The product was directly used in the next reaction step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][NH:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CNCCCN1CCCCC1
Product: CN(CCCN1CCCCC1)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N-methyl-3-(piperidin-1-yl)propyl amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=9.60 Hz, 1H) 1.66 (d, J=13.89 Hz, 3H) 1.82 (br. s., 2H) 2.01 (br. s., 2H) 2.83-3.13 (m, 7H) 3.32-3.58 (m, 4H) 7.79 (d, J=8.34 Hz, 2H) 8.13 (br. s., 3H) 8.58 (br. s., 3H) 9.05-9.50 (m, 1H) 12.43-14.49 (m, 1H). ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:30][C:31]1[C:32]([F:39])=[CH:33][C:34]([I:38])=[C:35]([OH:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:30][C:31]1[C:32]([F:39])=[CH:33][C:34]([I:38])=[C:35]([CH:36]=1)[O:37][C:8]1[CH:7]=[CH:6][C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1cc(Cl)c(F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3cc(Cl)c(F)cc3I)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 335 mg, 0.77 mmol) in dimethylsulfoxide (10 ml), was added 5-chloro-4-fluoro-2-iodophenol (Preparation 734, 200 mg, 0.73 mmol) and potassium carbonate (229 mg, 1.47 mmol). The flask was purged with nitrogen (3×). The resulting suspension was allowed to stir at room temperature for 18 hours. The reaction was poured into a 1M aqueous solution of sodium hydroxide, and extracted with dichloromethane (3×). The combined organic phase was then dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to leave the desired product as an off white solid (504 mg, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([C:31]([F:34])([F:33])[F:32])[N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([CH:15]3[CH:19]([OH:20])[CH2:18][N:17]([C:23]4[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([C:31]([F:33])([F:34])[F:32])[N:24]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O[C@@H]1CNC[C@H]1N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: Cc1nc(C(F)(F)F)nc(Cl)c1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)nc(N2CC(O)C(N3CCC(O)(c4ccc(Cl)cc4)CC3)C2)c1C

Procedure:
The title compound was prepared following general procedures described above from trans-4-(4-chloro-phenyl)-1-(4-hydroxy-pyrrolidin-3-yl)-piperidin-4-ol hydrochloride and 4-chloro-5,6-dimethyl-2-trifluoromethyl-pyrimidine in the presence of diisopropylethylamine and DMF. 1H-NMR (300 MHz, DMSO): δ 1.58 (2H, m), 1.89 (2H, m), 2.40 (3H, s), 2.60 (3H, m), 2.95 (2H, m), 3.32 (1H, m), 3.44 (1 H, m), 3.80 (2H, m), 4.32 (1H, m), 4.90 (1H, s), 5.20 (1H, d), 6.92 (1H, s), 7.42 (4H, dd). Retention Time (LC, method, AA standard): 1.75 min. MS (M+H+): 457
Reaction SMILES: [Mg].II.[CH2:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#N)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.C([O:31]CC)C>>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([C:23]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:31])[CH:25]=[CH:26][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCC
Reactant: N#Cc1cccc(OCc2ccccc2)c1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Product: O=C(Cc1ccccc1)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
A suspension of magnesium turnings (9 g) in dry diethyl ether (100 mL) containing a few crystals of iodine is treated with a solution of benzyl chloride (22.8 g) in diethyl ether (150 mL) at such a rate in the form of to maintain gentle reflux. After the addition is complete, the mixture is treated with 3-benzyloxybenzonitrile (12.7 g) and heated to reflux for 5 hours. The mixture is then treated with hydrochloric acid (1 N) until it is at pH 1, and stirring is continued for 1 hour at ambient temperature. The reaction mixture is separated and the aqueous layer extracted with diethyl ether (3×100 mL). The combined organic extracts are washed with water (3×100 mL), dried over magnesium sulphate and concentrated under reduced pressure. The resulting residue is recrystallised from methanol, to give benzyl 3-benzyloxyphenyl ketone (14.8 g), in the form of a white solid, m.p. 58-60° C. [Elemental analysis:- C,76.2; H,4.99%; Calculated:- C,76.28;H,4.99%].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2=[O:11].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([N:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:6]2=[O:11])[S:29]([CH3:28])(=[O:31])=[O:30])(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N)c2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN1C(=O)c2cccc(N(S(C)(=O)=O)S(C)(=O)=O)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of tert-butyl 2-(4-amino-1,3-dioxoisoindolin-2-yl)acetate (712 mg, 2.58 mmol), triethylamine (1029 μl, 7.73 mmol) and methanesulfonyl chloride (602 μl, 7.73 mmol) in 20 ml of DCM was stirred overnight at room temperature. The mixture was washed with 1N HCl, brine and finally dried over sodium sulfate and evaporated; the residue was purified by flash chromatography (Hexane/EtOAc 3/1 to 1/1) yielding tert-butyl 2-(4-(N-(methylsulfonyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate as an off-white foam (0.96 g, 2.220 mmol, 86% yield, MS/ESI+ 454.8 [MNa]+) and used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-methylphenol (101 mg, 0.71 mmol) was dissolved in tetrahydrofuran (2.1 mL) and the solution was treated with sodium hydride (60% dispersed in mineral oil, 31 mg, 0.78 mmol). After stirring for 30 minutes at 22° C., 2-chloro-5-nitropyridine (101 mg, 0.64 mmol) was added and the reaction mixture was heated to reflux for 1 hour. The solution was cooled to ambient temperature, quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2× with saturated NaHCO3, saturated NaCl, dried over anhydrous Na2SO4 and concentrated in vacuo.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.COC1C=C([CH2:47][N:48]2[CH2:53][CH2:52][N:51](C)[CH2:50][CH2:49]2)C=CC=1N.COCC(O)C>>[CH3:29][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18]([N:51]3[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]3)=[N:19]2)=[CH:14][CH:13]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: COc1cc(CN2CCN(C)CC2)ccc1N
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (89 mg, 0.20 mmol), N,N-Diisopropylethylamine (0.0757 mL, 0.435 mmol), 2-Methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (100 mg, 0.4 mmol) and 1-Methoxy-2-propanol (0.71 mL) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-Methyl-N-{2-[2-(4-methyl-piperazin-1-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide as a yellow solid. LCMS (E/I+) 401.20 (M+H). NMR 1H (DMSO-d6)-9.90 (bs, 1H), 8.99 (s, 1H), 7.88 (d, 1H, J=7.02 Hz), 7.65 (d, 1H, J=7.48 Hz), 7.45-7.54 (m, 2H), 7.00 (d, 1H, J=4.70 Hz), 6.92 (d, 1H, J=4.70 Hz), 4.45 (d, 2H, J=12.95 Hz), 3.49 (d, 2H, J=11.09 Hz), 3.03-3.25 (m, 7H), 2.89 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]#[N:21])=[C:10]([NH2:19])[N:11]([C:13]3C=CC=CC=3)[CH:12]=2)=[CH:4][CH:3]=1.CN([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]N=1)C.O.[CH:32]([NH2:34])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[C:10]([NH2:19])=[N:11][CH:13]=[N:21][C:20]=3[N:34]([C:32]3[CH:25]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2ccc(F)cc2)cn(-c2ccccc2)c1N
Reactant: CN(C)c1ccccn1
Reactant: NC=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(F)cc1)cn2-c1ccccc1
Temperature: 25 °C

Procedure:
4.78 g of 4-(4-fluorophenyl)-1-phenyl-2-amino-3-cyanopyrrole are heated at 180° C. with a spatula tipful of dimethylaminopyridine for 3.5 h in 50 ml of formamide under a nitrogen atmosphere. After cooling to RT, the mixture is treated with water and extracted 3 times with EA. The organic phases are washed with water, dried over Na2SO4 and concentrated. The residue is slurried with EA/ether and the crystals are filtered off. The crystals are suspended in hot ethanol and filtered off after cooling to RT. 5-(4-Fluorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine having a melting point of 202°-203° C. is obtained. 1H--NMR (d6 -DMSO): delta (ppm)=6.3 (br. s, 2H), 7.3-7.4 (m, 3H), 7.5-7.65 (m, 4H), 7.75 (s, 1H), 7.85 (d, 2H), 8.2 (s,1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])=[CH2:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]1=[N:8][C:7]=2[NH2:17])[CH3:2]
Reactant: C=Cc1cnc2c(N)nc3ccccc3c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cnc2c(N)nc3ccccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 2-vinylbenzo[f][1,7]naphthyridin-5-amine (Example 29) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-ethylbenzo[f][1,7]naphthyridin-5-amine as a solid. 1H NMR (methanol-d4): δ 8.78-8.81 (m, 2H), 8.45 (d, 1H), 7.55-7.63 (m, 2H), 7.35-7.40 (m, 1H), 2.97 (q, 2H), 1.43 (t, 2H). LRMS [M+H]=224.1.