Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([NH:6][S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)Nc1ccccc1
Temperature: -5 °C

Procedure:
25.2 g of chlorosulphonic acid are added slowly to a solution of 60.6 g of aniline in 316 ml of methylene chloride cooled to −5° C. When the addition is complete, the mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off. After drying, the precipitate is taken up in 231 ml of toluene, and 45.1 g of phosphorus pentachloride are added gradually. The mixture is then refluxed for 3 hours 30 minutes and, after returning to ambient temperature, the precipitate formed is filtered off. The filtrate is concentrated to obtain the expected product.
Reaction SMILES: [I-].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br-:20].[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][C:29]=1[CH3:37])([OH:23])=[O:22].[Br-].CC1SC2C=CC=CC=2[NH+]=1>C(Cl)Cl>[Br-:20].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:37]=[C:29]2[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]([OH:23])=[O:22])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30]2)=[CH:5][CH:4]=1
Reactant: Cc1sc2ccccc2[n+]1CCCCC(=O)O
Reactant: C[n+]1cccc2ccccc21
Agent: Cc1[nH+]c2ccccc2s1
Agent: [Br-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[n+]1ccc(C=C2Sc3ccccc3N2CCCCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Next, 1.36 g (5.0 mmol) of N-methylquinolinium iodide (Compound III) (FW 271.10), 7.0 mL (50 mmol) of triethylamine (FW 101.19, d=0.726), and 100 mL of methylene chloride were added to 3.24 g of mixture (crude product) containing Compound 112 (3-(4-carboxybutyl)-2-methylbenzothiazolium bromide) and 2-methylbenzothiazolium bromide. As a result, a transparent solution was obtained. This solution was stirred at 25° C. for 16 hours. Thereafter, the solvent was evaporated under reduced pressure. Acetone (200 mL) was then added to the residue and the precipitate obtained thereby was filtered, which then was washed with acetone. The residue thus obtained was dried under reduced pressure, and the red residue obtained after drying was washed with distilled water (50 mL). This further was filtered, which was washed with distilled water and then dried under reduced pressure. Thus a target substance (Compound 107) was obtained as red powder (654 mg, 1.39 mmol, 28%). This red powder was confirmed to be the target substance (Compound 107) through a comparison in 1HNMR spectrum with the reference value. Peak values from 1HNMR and 13CNMR (DMSO-d6) and the measured values of HRMS (ESI) are indicated below. Furthermore, FIG. 6 shows the 1HNMR spectrum (DMSO-d6) of Compound 107. Compound 107: 1HNMR (DMSO-d6): δ 8.74 (d, J=8.3 Hz, 1H), 8.51 (d, J=7.3 Hz, 1H), 7.94-7.89 (m, 3H), 7.74-7.70 (m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.55-7.51 (m, 1H), 7.36-7.32 (m, 1H), 7.21 (d, J=7.3 Hz, 1H), 6.83 (s, 1H), 4.47 (t, J=7.1 Hz, 2H), 4.07 (s, 3H), 2.22 (t, J=6.6 Hz, 1H), 1.77-1.63 (m, 4H);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]([C:14]2[N:15]([CH2:25][C:26]3[CH:31]=[C:30]([NH:32]CC4C=CC(OC)=CC=4)[N:29]=[C:28]([F:42])[CH:27]=3)[C:16](=[O:24])[NH:17][C:18](=[O:23])[C:19]=2[CH:20]([CH3:22])[CH3:21])[C:11](=[O:13])[CH3:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1)#[N:2].C(O)(=O)C.[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[NH2:32][C:30]1[CH:31]=[C:26]([CH2:25][N:15]2[C:14]([N:10]([C:5]3[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)[C:11](=[O:13])[CH3:12])=[C:19]([CH:20]([CH3:22])[CH3:21])[C:18](=[O:23])[NH:17][C:16]2=[O:24])[CH:27]=[C:28]([F:42])[N:29]=1
Reactant: COc1ccc(CNc2cc(Cn3c(N(C(C)=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N(c1cc(C)cc(C#N)c1)c1c(C(C)C)c(=O)[nH]c(=O)n1Cc1cc(N)nc(F)c1
Yield: 51 %

Procedure:
A solution of N-(3-cyano-5-methyl-phenyl)-N-{3-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl}-acetamide (58 mg, 0.10 mmol) in acetonitrile (0.7 mL) was treated with glacial acetic acid (0.275 mL), cerric (IV) ammonium nitrate (111 mg, 0.20 mmol) and water (10 drops). After 30 min the mixture was partitioned between water (5 mL) and ethyl acetate (10 mL). The solvent was removed from the organic phase in vacuo and the residue was subjected to flash chromatography (eluant: 0-70% ethyl acetate/hexanes). The product containing fractions were combined and the solvent was removed in vacuo to yield the product (23 mg, 0.051 mmol). C23H23FN6O3 calculated 450.2, observed [M+1]+451.1; rt=3.08 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:9])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(NC(=O)c2cnc(Cl)c(Cl)c2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 5,6-dichloronicotinic acid and 4-methoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 15. 1H NMR (DMSO-d6): 10.85 (bs, 1H), 8.88 (d, J=2.4, 1H), 8.59 (d, J=2.4, 1H), 7.58-7.54 (m, 2H), 7.39-7.35 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCCCCN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 100.5 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-{5-[4-(t-butoxycarbonyl-n-hexylamino)phenoxy]-2-nitrophenyl}-N-methylcarbamate (13.8 g), palladium on carbon (10%, 1.0 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (13.1 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[C:39]([Cl:40])=[C:38]([CH3:41])[NH:37][C:36]=1[C:42](NC1CCN(C2C=C(C3N=CON=3)C=C(Cl)N=2)CC1)=[O:43].Cl.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([C:71]2[N:76]=[C:75]([S:77][CH3:78])[N:74]=[C:73]([NH2:79])[CH:72]=2)[CH2:67][CH2:66]1>CN(C=O)C>[NH2:79][C:73]1[N:74]=[C:75]([S:77][CH3:78])[N:76]=[C:71]([N:68]2[CH2:69][CH2:70][CH:65]([NH:64][C:42]([C:36]3[NH:37][C:38]([CH3:41])=[C:39]([Cl:40])[C:35]=3[Cl:34])=[O:43])[CH2:66][CH2:67]2)[CH:72]=1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CSc1nc(N)cc(N2CCC(N)CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1nc(N)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
Diisopropylethylamine (0.21 ml, 1.25 mmol) and HATU (0.239 g, 0.63 mmol) were added to a stirred solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) (0.122 g, 0.63 mmol) in DMF (2 ml). The resultant solution was stirred for 5 minutes, 6-(4-amino-piperidin-1-yl)-2-(methylthio)pyrimidin-4-amine hydrochloride (Intermediate 46) (0.2 g, 0.63 mmol) was added and the mixture was stirred at room temperature for 18 h. The crude mixture was filtered and purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) to give the title product (42 mg).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:55])[C@H:10]([O:24][C:25]1[C:30]([Br:31])=[CH:29][C:28]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]4[CH:53]=[CH:52][CH:51]=[CH:50][C:40]=4[S:41][C:42]=3[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:27][C:26]=1[Br:54])[CH2:11][CH2:12][N:13]1C(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].CO.Cl>O>[CH2:43]([C:42]1[S:41][C:40]2[CH:50]=[CH:51][CH:52]=[CH:53][C:39]=2[C:38]=1[C:35]1[CH:36]=[CH:37][C:32]([C:28]2[CH:27]=[C:26]([Br:54])[C:25]([O:24][C@@H:10]([C:9]([O:8][CH3:7])=[O:55])[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]([OH:3])=[O:4])=[C:30]([Br:31])[CH:29]=2)=[CH:33][CH:34]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](CCNC(=O)c1ccccc1C(=O)O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 624.3 %

Procedure:
Potassium carbonate (0.01 g) was added into a mixture of (2R)-2-[4′-(2-benzyl-benzo[b]-thiophen-3-yl)-3,5-dibromo-biphenyl-4-yloxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (0.5, 0.063 mmol), methyl alcohol (10 mL), and water (0.5 mL). The reaction mixture was stirred at room temperature for 24 hours, poured into water, acidified with HCl (2 N), and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtAOc 4:1) gave white solid (0.32 g, 63% yield): mp 95-97° C; MS m/e 811 (M+);
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)([Cl:13])=O>ClC1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCC(=O)O
Solvent: Clc1ccccc1
Product: CCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
86.6 g (0.6 mol) of octanoic acid and 890 g of monochlorobenzene are introduced into the reactor and 600 g (6.07 mol) of phosgene are then added over about 30 minutes, while maintaining the temperature of the reaction medium at a maximum of 25° C. The set pressure is adjusted to 10.5 bar relative and the reaction medium is heated. After two hours, the level of residual acid is about 1 mol %, the level of residual anhydride is zero and the level of octanoyl chloride obtained is 99 mol %.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH3:32][N:33]([CH3:38])[CH2:34][C:35]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=3)[N:9]=2)[CH2:3]1)=[O:36]
Reactant: CN(C)CC(=O)O
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Yield: 41.8 %

Procedure:
A solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (40 mg, 0.094 mmol), 2-(dimethylamino)acetic acid (19.43 mg, 0.188 mmol), N,N-diisopropylethylamine (0.033 mL, 0.188 mmol), and HATU (71.7 mg, 0.188 mmol) in DMF was stirred at rt for 1 h. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to obtain 20 mg of (R)-6-(3-(2-(dimethylamino) acetamido)piperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a light yellow solid. LCMS: (M+H)+=510.40. 1H NMR (400 MHz, CDCl3) δ ppm 11.21 (1H, s), 7.69 (2H, d, J=8.56 Hz), 7.53 (1H, d, J=9.06 Hz), 7.37 (2H, d, J=8.56 Hz), 7.30 (1H, d, J=7.81 Hz), 6.12 (1H, d, J=8.81 Hz), 5.60 (1H, s), 3.96 (1H, dd, J=13.22, 3.15 Hz), 3.78-3.88 (1H, m), 3.60-3.78 (8H, m), 3.41-3.56 (2H, m), 2.92 (2H, s), 2.22 (6H, s), 1.65-2.03 (4H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Br[CH2:8][C:9]([NH:11][C:12]1[C:29]([OH:30])=[C:28]2[C:15]([CH2:16][CH:17]3[C:26]([C:27]2=[O:31])=[C:25]([OH:32])[C:24]2([OH:33])[CH:19]([CH:20]([N:39]([CH3:41])[CH3:40])[C:21]([OH:38])=[C:22]([C:35]([NH2:37])=[O:36])[C:23]2=[O:34])[CH2:18]3)=[C:14]([N:42]([CH3:44])[CH3:43])[CH:13]=1)=[O:10]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:41][N:39]([CH3:40])[C@H:20]1[C@H:19]2[C@:24]([OH:33])([C:25]([OH:32])=[C:26]3[C@H:17]([CH2:18]2)[CH2:16][C:15]2[C:28](=[C:29]([OH:30])[C:12]([NH:11][C:9](=[O:10])[CH2:8][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:13][C:14]=2[N:42]([CH3:43])[CH3:44])[C:27]3=[O:31])[C:23](=[O:34])[C:22]([C:35]([NH2:37])=[O:36])=[C:21]1[OH:38]
Reactant: C1CCONC1
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: CN(C)c1cc(NC(=O)CN2CCCCO2)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Yield: 39.6 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 2 g of [1,2]oxazinane, and 0.5 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2 ml acetonitrile to give 0.2 g of the product.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[N:13]1([CH2:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[ClH:1].[N:13]1([CH2:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[O:23][CH2:24][CH2:25][CH2:26][NH:27][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: NCCCOc1cccc(CN2CCOCC2)c1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=S1(=O)N=C(NCCCOc2cccc(CN3CCOCC3)c2)c2ccccc21
Reaction time: 0.25 h

Procedure:
A solution of 1.37 g (0.0068 moles) of 3-chlorobenzoisothiazole 1,1-dioxide is added dropwise to 1.7 g (0.0068 moles) of 3-[3-(4-morpholinylmethyl)phenoxy]-1-propanamine in 150 ml of gently refluxing chloroform, over 30 minutes. The reflux is continued for 15 minutes after the end of the addition, then the reaction mixture is evaporated to dryness. The residue is treated with ethanol-ethyl acetate, causing the formation of a yellow-white solid. m.p. 21° C. (dec.) Recrystallization of the crude product from ethanol gave a m.p. of 215° C. (dec.) (1.7 g yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26]Br)[CH3:22]>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][CH2:26][CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:28])=[N:5][N:6]=1
Reactant: CCOC(=O)CCBr
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 60 °C

Procedure:
To a solution of 5-Amino-4-(4-cyclopropyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (0.35 g, 1.239 mmol) in DMF (2.5 mL) was added 3-Bromo-propionic acid ethyl ester (158 μL, 224 mg; 1.239 mmol) and heated to 60° C. for 20 hours. The reaction mixture was concentrated and sonicated with ethyl ether several times, decanting the ethyl ether layer. The resulting light yellow oil was placed on high vacuum to afford crude ethyl 3-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate as a light brown oily foam which was used directly in the next step (0.409 g, 87%).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].O.Cl.[Cl:9][C:10]1(CCl)[CH:15]=[CH:14][CH:13]=[N:12][CH2:11]1.[CH2:18](O)C>>[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[CH2:18][S:1]([OH:4])(=[O:3])=[O:2]
Reactant: ClCC1(Cl)C=CC=NC1
Reactant: O=S([O-])[O-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)Cc1ccncc1Cl

Procedure:
A suspension of sodium sulfite (75.90 g, 0.602 mol) in a solution of water (240 ml) and ethanol (60 ml) was treated at ambient temperature with solid 3-chloro-3-chloromethylpyridine hydrochloride (59.77g, 0.301 mol). The resulting mixture was heated in an oil bath to reflux.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[CH3:28][N:29]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=1)[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31].[F-].[Cs+]>COCCOC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([N:29]([CH3:28])[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:43]=1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: CN(C(=O)N1CCOCC1)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(-c2cccc(N(C)C(=O)N3CCOCC3)c2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.0 g, 2.40 mmol) was, dissolved in 1,2-dimethoxyethane (14.4 ml) and ethanol (1.6 ml). N-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine-4-carboxamide (0.914 g, 2.64 mmol) was added and argon was bubbled in the solution for 10 minutes. Cesium fluoride (0.80 g, 5.28 mmol) and palladium tetrakistriphenylphosphine (0.139 g, 0.12 mmol) were added and the mixture was heated to reflux under an argon atmosphere for 14 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate and water. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3) giving 0.232 g (20%) of the desired product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N+:12]([O-])[CH:11]=[CH:10]2>ClCCCl>[Cl:3][C:13]1[C:14]2[C:9](=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([CH3:6])=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Solvent: ClCCCl
Product: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Temperature: 70 °C
Yield: 85.9 %

Procedure:
Phosphorous oxychloride (2.15 mL, 23.0 mmol) was added dropwise to a solution of 6-methyl-5-nitroisoquinoline N-oxide (0.940 g, 4.60 mmol) in 1,2-dichloroethane (40.0 mL). The mixture was heated to 70° C. for 3 h to afford an off-white suspension. The mixture was concentrated and the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-chloro-6-methyl-5-nitroisoquinoline (0.880 g, 86% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 223.0 [M+H]+
Reaction SMILES: ClC1N=C2C(NC=N2)=C(Cl)N=1.C(N1C=NC2C1=NC=NC=2)=C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([P:30](=[O:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][N:50]2[CH:53]=[CH2:54])=[C:46](Cl)[N:45]=1>CCO>[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][N:50]2[CH:53]=[CH2:54])=[C:46]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([P:30]([CH3:31])([CH3:32])=[O:33])=[CH:28][CH:29]=2)[N:45]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: C=Cn1cnc2c(Cl)nc(Cl)nc21
Agent: C=Cn1cnc2cncnc21
Agent: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21

Procedure:
To a sealed tube were added 2,6-dichloropurine-9-vinyl purine (0.43 g, 2 mmol), 4-aminophenyl-dimethylphosphine oxide (0.37 g, 2.2 mmol), and the solids were dissolved in ˜15 mL anhydrous EtOH under Ar. Then DIEA (1.0 mL, 6 mmol) was added. The reaction was heated at 105° C. for 3 overnights until the starting material 2,6-dichloro-9-vinylpurine had disappeared. Volatiles were removed by rotavaporing and the residue was partitioned between EtOAc/water. The organic layer was washed with water once more and dried over Na2SO4. The final product was purified by silica gel column chromatography (4˜8% MeOH/DCM).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#N.CC(C[AlH]CC(C)C)C.Cl.C1C[O:35]CC1>>[CH:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:35]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)nc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-(6-cyano-pyridin-3-yl)-piperazine-1-carboxylate (2.15 mmol) in THF (20 mL) is added a solution of DIBAL-H in THF (1.0 M, 13 mmol) dropwise and the reaction mixture is stirred at room temperature for 15 minutes. After it is cooled to 0° C., the reaction mixture is mixed with a solution of aqueous HCl (2 N, 5 mL) after which the reaction mixture is partitioned between saturated Na2CO3 solution and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (3:7 hexanes/EtOAc) to give tert-butyl 4-(6-formyl-pyridin-3-yl)-piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:3]=1.FC(F)(F)[CH2:31][O:32]S(C(F)(F)F)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH2:10][C:9]3[N:14]=[CH:31][O:32][N:8]=3)[CH2:24]2)[CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCNC3)c12
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCN(Cc4ncon4)C3)c12

Procedure:
The following compound was prepared analogously to example 72 from 4-[4-fluoro-2-((R)-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester.