Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:29][C:20]1[C:19]2[N:18]=[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 4-fluorophenylisocyanate (0.137 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol: The resulting pale yellow precipitate (identified as the bis-adduct) was isolated by filtration. The filtrate was concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.22 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(4-fluorophenyl)urea as a white solid, m.p. 145–150° C. Mass spec M+1=469.2. Analysis: C27H25FN6O: % C, 69.21; % H, 5.37; % N, 17.94; Found: % C, 66.70; % H, 5.33; % N, 17.03.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)[NH:10][C:11]2[CH2:12][O:13][CH2:14][C:15]([F:41])([F:40])[C@:16]([C:19]3[CH:24]=[C:23]([N:25]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:22]=[CH:21][C:20]=3[F:39])([CH3:18])[N:17]=2)=CC=1.FC(F)(F)C(O)=O>ClCCl.O1CCOCC1.Cl>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([F:39])=[C:19]([C@:16]2([CH3:18])[C:15]([F:40])([F:41])[CH2:14][O:13][CH2:12][C:11]([NH2:10])=[N:17]2)[CH:24]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N=C(c4ccccc4)c4ccccc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reaction time: 1 h

Procedure:
To a solution of crude (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-(diphenylmethyleneamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.2 mmol) in dichloromethane (20 ml) was added at 22° C. trifluoroacetic acid (2.6 ml) and stirring was continued for 1 h. The mixture was diluted with 1,4-dioxane (40 ml) and aqueous hydrochloric acid (1 M, 33 ml) and vigorous stirring of the emulsion at 22° C. was continued for 16 h. The mixture was evaporated and the residue partitioned between saturated aqueous NaCl and ethyl acetate, the aqueous layer was separated, the pH was adjusted to 14 using saturated aqueous Na2CO3 solution and extracted with ethyl acetate. The organic layer was dried, evaporated and the residue purified by chromatography on silica-NH2 using dichloromethane to give (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine as a colorless oil. MS (ISP): m/z=274.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:25]([NH:24][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:21][N:22]=2)[N:19]=1
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added the isocyanatobenzene (2.5 mg, 0.021 mmol) in DCM (0.1 mL) dropwise. The reaction was slowly warmed to ambient temperature and stirred for 1 hour. The reaction was diluted with DCM (2 mL), washed with water, and concentrated. The crude product was purified by silica gel chromatography (eluent=50% EtOAc/hexanes first, then 5% MeOH in DCM) to yield the pure final product as a solid (5 mg, 60%). MS (apci) m/z=435.2 (M+H).
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[C:6]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([CH:10]=[C:11]([F:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]=[O:9].[CH3:30]COCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[F:4][C:5]1[C:6]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:7]([CH:8]([OH:9])[CH3:30])[CH:10]=[C:11]([F:21])[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1OCc1ccccc1
Agent: C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(O)c1cc(F)c(OCc2ccccc2)c(F)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (3.0M solution in ether, 1.1 eq) is added to a 0.4M solution of Compound 23 in ether (1.0 eq) at 0° C. The reaction is stirred at 0° C. for 1 hour, then warmed to 20° C. for an additional hour, and poured into 5 volumes of 1M citric acid solution. The resulting solution is extracted with ether (2×), washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue is purified by chromatography on silica gel (Hex/EtOAc) to yield Compound 24.
Reaction SMILES: Cl.[NH2:2]O.[Br:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH:16]=O)=[CH:10]2>CS(C)=O.C(OCC)(=O)C>[Br:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([C:16]#[N:2])=[CH:10]2
Reactant: O=Cc1ccc2c(Br)cc(F)cc2c1
Reactant: NO
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(Br)cc(F)cc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
Hydroxylamine hydrochloride (0.5 g, 7.9 mmol) was added to a solution of 32 (1.0 g, 4.0 mmol) in DMSO (5.0 mL), and the mixture was stirred for 16 h at 100° C. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL), and washed with saturated NaHCO3 aqueous solution (2×50 mL). The organic was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and purified by column chromatography to give 5-bromo-7-fluoro-2-naphthonitrile (33) (28%). 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.0, 2.3 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H). GC-MS (ES) for C11H5BrFN [M+1]+ 250.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]#[N:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:24][S:21]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:10]#[N:11])=[C:7]([O:8][CH3:9])[C:2]=1[Cl:1])(=[O:23])=[O:22]
Reactant: COc1c(C#N)ccc(CCO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C#N)ccc(CCOS(C)(=O)=O)c1Cl
Reaction time: 2 h

Procedure:
A solution of 2-(2-chloro-4-cyano-3-methoxyphenyl)ethanol (205 mg, 0.969 mmol) DIPEA (0.846 mL, 4.84 mmol) and pyridine (0.078 mL, 0.969 mmol) in DCM (3 mL) was treated dropwise with mesyl chloride (0.110 mL, 1.417 mmol). The reaction was stirred for 2 hours and was then diluted with DCM and washed twice with aq. citric acid, then washed with brine, and dried over sodium sulfate. The residue was purified by flash chromatography (20-50% ethyl acetate/hexanes) to afford the title intermediate.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[C:37]([F:39])[C:36]([O:40][CH3:41])=[CH:35][C:34]=1[F:42])[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:42][C:34]1[CH:35]=[C:36]([O:40][CH3:41])[C:37]([F:39])=[CH:38][C:33]=1[C@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH2:18][NH:19][CH3:32]
Reactant: COc1cc(F)c([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1F
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(OC)cc1F

Procedure:
Compound 32 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [389 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 10.03-9.86 (m, 1H), 9.04 (s, 1H), 8.98 (d, J=4.5 Hz, 1H), 8.56 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.24-8.07 (m, 1H), 7.42 (dd, J=12.1, 7.0 Hz, 1H), 7.09 (dd, J=11.5, 7.2 Hz, 1H), 5.72 (s, 1H), 3.82 (s, 3H), 3.11 (dd, J=12.3, 8.5 Hz, 1H), 2.85 (dd, J=12.4, 5.3 Hz, 1H), 2.54 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([F:14])[C:3]=1[F:15].O=P(Cl)(Cl)Cl.O>C(#N)C>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]#[N:8])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: NC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])c(N)c(F)c1F
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred suspension of 4-amino-2,3-difluoro-5-nitrobenzamide (90 g, 0.416 mol) in acetonitrile (630 mL) was added POCl3 (96 mL, 1.04 mol) in one portion. The mixture was then heated to 70° C. and as the reaction proceeded the suspension become a brown solution. After 1.5 hours, HPLC analysis showed no remaining starting material. The reaction mixture was cooled to 30° C., then added to water (4.5 L) over 30 minutes while the temperature was held at 17-25° C. The resultant bright yellow slurry was stirred for 1 hour, filtered under vacuum, and the remaining solid was then dried in a vacuum oven at 50° C. to provide 4-amino-2,3-difluoro-5-nitrobenzonitrile as a yellow solid, (74.4 g, 90% yield). HPLC 95a %. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (2H, br s, NH2), 8.53 (1H, apparent dd, J 1.8, 6.4, Ar—H). 19F NMR (376 MHz, DMSO-d6) δ −128, −152. 13C (100 MHz, DMSO-d6) δ 87.1 (C, d, J 15), 113.6 (C, d, J 4), 128.6 (CH, s), 128.8 (C, d, J 5), 139.3 (CF, dd, J 245, 14), 141.5 (C, dd, J 13, 5), 152.8 (CF, dd, J 259, 12). IR νmax/cm−1 3446, 3322, 2235, 1647, 1551, 1287, 1275. MS APCI (−) 198 (M−1) detected, APCI (+) 200 (M+1) detected.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[S:8][C:9]2[C:10](=[CH:12][C:13]3[N:14]=[C:15]([NH2:19])[S:16][C:17]=3[CH:18]=2)[N:11]=1>CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:19][C:15]1[S:16][C:17]2[C:13](=[CH:12][C:10]3[N:11]=[C:7]([NH2:6])[S:8][C:9]=3[CH:18]=2)[N:14]=1)=[O:4]
Reactant: Nc1nc2cc3nc(N)sc3cc2s1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Product: Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1

Procedure:
1.2 gm of chloroacetyl chloride were added to a stirred solution of 2.2 gm of 2,6-diamino-benzo[1,2-d:5,4-d']bisthiazole in 20 ml of dimethylformamide at 5° C. The resulting suspension was heated for 1 hour on a waterbath, then cooled, and the solid 2,6-bis-(chloroacetyl-amino)-benzo[1,2-d:5,4-d']bisthiazole was filtered off. While stirring, 0.5 gm of an aqueous saturated sodium carbonate solution was added to the filtrate. After 1 hour the precipitate was filtered off, dissolved in 30 ml of dimethylformamide/dioxan (1:1), freed from traces of insoluble material and precipitated again with water. The crystals were dissolved in dimethylformamide and the solution was treated with an excess of 2 N hydrochloric acid. The hydrochloride obtained thereby was washed and dried.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][NH:31]2)[CH2:28]1)=[O:26].Cl[C:41]1[N:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=1>>[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:33][CH:32]2[CH:29]([CH2:30][N:31]2[C:41]2[N:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=2)[CH2:28]1)=[O:26]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Reactant: COc1ccnc(Cl)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: COc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to for Intermediate 2, Step A, using Intermediate 19 and 2-chloro-4-methoxypyrimidine. MS (ESI) mass calcd. for C23H22N4O2, 386.46; m/z found, 387.2 [M+H]+.
Reaction SMILES: C([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18](Cl)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=O.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:17][O:16][C:14]1[C:15]2[NH:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[C:11]([S:18]([NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:19])=[O:20])=[CH:12][CH:13]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(S(=O)(=O)Cl)c2c3ccccc3n(C=O)c12
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccncc2)c2c1[nH]c1ccccc12
Temperature: 100 °C
Yield: 41 %

Procedure:
Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 5 ml of pyridine. To it was added 4-aminopyridine (0.35 g, 3.7 mM) and the reaction mixture was heated at 100° C. for three hours. The solvent was evaporated and the residue was purified on a silica gel column using MeOH(CHCl3 to obtain the deformylated desired compound as a white solid with a yield of 41% (0.097 g); mp 311-313° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O)[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:40])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.Cl>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:4][C:3]=1[NH:19][C:20](=[O:40])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)ccc1NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(OCCN)ccc1NC(=O)c1ccc(N2CCNCC2)cc1
Reaction time: 1 h
Yield: 120.4 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar and a gas dispersion tube was added N-(2-methyl-4-(2-(1,1-dimethylethoxycarbonylamino)ethoxy)phenyl)-4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)benzamide (0.912 g, 1.64 mmol) and 100 mL of dry EtOAc. This well stirred solution was cooled in an ice bath and saturated with HCl gas over 15 min. The mixture was aged 1 h at 0° C. and the excess HCl was then removed with a stream of argon. The EtOAc was removed in vacuo and the crude product was recrystallized from MeOH-EtOAc to give 0.70 g of N-(2-methyl-4-(2-aminoethoxy)phenyl)-4-(1-piperazinyl)benzamide, dihydrochlorlide as a white solid. mp:>250° C. 1H NMR (CD3OD): d 2.27 (s, 3H), 3.29 (m, 1H), 3.30 (m, 6H), 3.57 (m, 4H), 4.24 (t, j=5 Hz, 3H), 6.87 (dd, j=5,9 Hz, 1H), 6.94 (d, j=5 Hz, 1H), 7.12 (d, j=9 Hz, 2H), 7.22 (d, j=9 Hz, 1H), 7.91 (d, j=9Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:15]N1C(=O)CCC1=O>O1CCCC1>[Br:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 1H-indole-2-carboxylate (9.45 g) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (8.89 g, 50 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was dissolved with water (100 ml) and diethyl ether (300 ml). The organic layer was washed with water brine and dried over Na2SO4. After filtration, concentration of solvent afforded the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[C:21](=O)[C:22]([N:24]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:40]=[C:41]=[N:42][Si](C)(C)C)(C)C.Cl>C(#N)C.ClCCl>[NH2:40][C:41]1[N:42]=[C:21]([C:22]([N:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:32]2)=[O:23])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=2)[N:8]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4.9 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxo-acetyl)phenyl]acetate are dissolved in 100 ml of acetonitrile under argon. 1.7 g of caesium fluoride are added, and 3 ml of bis(trimethylsilyl)carbodiimide are added dropwise to the solution over the course of 5 min. The mixture is stirred at room temperature for 15 min, and 20 ml of dichloromethane are then added. After addition of 20 ml of hydrochloric acid (1N), the product precipitates out as white solid.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([NH:9][NH2:10])[CH2:5][CH2:4]1.CN1CCCC1=O.CCN(C(C)C)C(C)C.[Br:27][C:28]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:31]([NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[C:30]([C:45](=O)/[CH:46]=[CH:47]/N(C)C)[CH:29]=1>O>[Br:27][C:28]1[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][C:31]([NH:38][C:39](=[O:44])[C:40]([F:41])([F:42])[F:43])=[C:30]([C:45]2[N:9]([CH:6]3[CH2:7][CH2:8][O:3][CH2:4][CH2:5]3)[N:10]=[CH:47][CH:46]=2)[CH:29]=1
Reactant: NNC1CCOCC1
Reactant: CN(C)/C=C/C(=O)c1cc(Br)c(C(F)(F)F)cc1NC(=O)C(F)(F)F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(F)(F)F)c(Br)cc1-c1ccnn1C1CCOCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.1 %

Procedure:
To a mixture of 6.0 g of tetrahydro-2H-pyran-4-ylhydrazine dihydrochloride and 175 mL of N-methylpyrrolidone was added 11 mL of DIPEA, followed by stirring at room temperature for 20 minutes. To the reaction mixture was added 8.86 g of N-{4-bromo-2-[(2E)-3-(dimethylamino)prop-2-enoyl]-5-(trifluoromethyl)phenyl}-2,2,2-trifluoroacetamide, followed by stirring at 110° C. for 1 hour. To the reaction mixture was added water, followed by extraction with isopropyl acetate, and the organic layer was washed with saturated brine. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol). The obtained oil was triturated with diethyl ether/n-hexane to obtain 4.19 g of N-{4-bromo-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-5-(trifluoromethyl)phenyl}-2,2,2-trifluoroacetamide.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([CH: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.BrC1C=C[N:26]2[CH:29]=[N:30][N:31]=C2C=1>>[N:31]1[N:30]=[CH:29][N:26]2[CH:4]=[CH:5][C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]3)=[CH:7][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: Brc1ccn2cnnc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccn3cnnc3c2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.1, except 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (compound 41.2) was used in place of 4-bromobenzonitrile. m/z (ES+) 303 (M+H)+.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[F:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([NH2:23])=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])[C:15]=1[F:33].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[F:33][C:15]1[C:16]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:6](=[O:7])[NH:23][C:17]=2[C:18]2[O:22][CH:21]=[CH:20][C:19]=2[C:14]=1[F:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Temperature: 30 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
CDI (0.144 g, 0.891 mmol) was added to a solution of 4,5-difluoro-N6-(2-fluoro-4-iodo-phenyl)-benzofuran-6,7-diamine (I-31a: 0.240 g, 0.5940 mmol) in dry DCM (5 mL). The reaction mass was stirred 12-16 hours at 20-40° C. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) afforded 0.180 g of the product (70% yield). 1H NMR (DMSO-d6, 300 MHz): δ 12.15 (bs, 1H), 8.12 (d, 1H), 7.95 (dd, 1H), 7.79 (d, 1H), 7.50 (t, 1H), 7.21 (d, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH3:24])[C:10]([O:12]CC)=[O:11].[OH-].[Li+].O>C(Cl)Cl.C1COCC1>[CH3:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:17]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1ccc(N2CCCCC2C)c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC1CCCCN1c1ccc(C(=O)O)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
Methanesulfonyl chloride (1.68 mL; 21.72 mmol) was added dropwise (addition took 5 min) to a cold (0° C.) solution of Py (10 mL) and ethyl 3-amino-4-(2-methylpiperidin-1-yl)benzoate (5.18 g; 19.74 mmol) in DCM (40 mL) and the reaction mixture was allowed to return to RT over one hour. The reaction mixture was stirred at RT for 3 hours. After this time, it was concentrated and the residue was taken up in water. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with HCl (1 M) then brine, dried over MgSO4 and concentrated giving a yellow oil. This oil was taken up in THF (30 mL) and lithium hydroxide (2.36 g; 98.72 mmol) was added, followed by water (30 mL). The resulting mixture was stirred at RT for 2 days. THF was removed under vacuum and the solution diluted with water. This solution was washed with Et2O and acidified to pH 2 with conc HCl. The aqueous phase was extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid (5.48 g, 88%). 1H NMR (DMSO-d6) δ 12.98 (br s, 1H), 8.53 (br s, 1H), 8.07-8.06 (d, J=1.91 Hz, 1H), 7.77-7.73 (dd, J=8.34 Hz, 1.97 Hz, 1H), 7.47-7.45 (d, J=8.34 Hz, 1H), 3.43-2.58 (m, 6H), 1.84-1.46 (m, 6H), 0.83-0.81 (d, J=6.09 Hz, 3H). HPLC (Method A) Rt 2.29 min (Purity: 99.0%).