Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][OH:12].O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][O:12][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: CN1c2ccccc2CC1CO
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CN1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Yield: 70.7 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 2.0 g of 1-methylindolin-2-ylmethanol (prepared as described in Preparation 6), 4.73 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.53 ml of tributylphosphine, 2.57 g of 1,1'-(azodicarbonyl)dipiperidine and 55 ml of benzene were used, to give 4.39 g of the title compound, melting at 62.5-65.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[CH:14][C:13]([OH:19])=[CH:12][C:11]=3[OH:10])=[N:21][NH:22][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)ccc12
Solvent: O
Solvent: CCO
Product: Oc1ccc(-c2n[nH]cc2-c2ccc(Br)cc2)c(O)c1

Procedure:
This compounds was synthesised in the same manner as described in the preceding experiment. 3-(4-Bromo-phenyl)-7-hydroxy-chromen-4-one (0.1 g, 0.3 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude solid product was washed in hot ether to give 4-[4-(4-Bromo-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.069, 60.6%); Rf 0.44 Cf SM 0.79 ethyl acetate/hexane (75/25).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6](OCC)(OCC)([O:8][CH2:9][CH3:10])[CH3:7]>>[CH2:6]([O:8][C:9](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:10])[CH3:7]
Reactant: N#CCC#N
Reactant: CCOC(C)(OCC)OCC
Product: CCOC(C)=C(C#N)C#N

Procedure:
8.26 g (125 mmol) of malononitrile and 20.25 g (125 mmol) of triethyl orthoacetate are refluxed for hours. After cooling, the mixture is dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (15 g, 61 mmol) and dihydro-2H-pyran-4(3H)-one (9.2 g, 92 mmol) in dichloroethane (300 mL), acetic acid (22 g, 368.4 mmol) was added and the reaction stirred at room temperature for 2 h. Then sodium triacetoxyborohydride (39 g, 184 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography to afford the title compound (14 g, 69%).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH2:22])=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: NC(=O)c1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(N)=O)c2)cc1
Yield: 85.8 %

Procedure:
To a solution of (4-tert-butyl-phenoxy)acetic acid (125 mg, 0.6 mmol), 3-amino benzamide (163.5 mg, 1.2 mmol), HOBT (162 mg, 1.2 mmol) and DIPEA (155 mg, 1.2 mmol) in DMF (6 ml) was added EDC (230.05 mg, 1.2 mmol) at room temperature and the resulting mixture was stirred until reaction completion as indicated by TLC. Reaction mixture was poured onto ice cold water, diluted with a mix of MeOH:MC (10%), separated organic layer and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified flash chromatography on silica gel (MeOH:MC=1:9˜2:8) to afford of 3-[2-(4-tert-butyl-phenoxy)-acetylamino]-benzamide as a colorless solid (168 mg, 85.75% yield).
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH2:9][O:10][CH3:11])[C:3](OCC)=[O:4].C[O-].[Na+].[NH2:16][C:17]([NH2:19])=[NH:18].S(=O)(=O)(O)O>CN(C)C=O.C(O)C>[NH2:19][C:17]1[N:18]=[C:3]([OH:4])[C:2]([CH3:1])=[C:8]([CH2:9][O:10][CH3:11])[N:16]=1
Reactant: CCOC(=O)C(C)C(=O)COC
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COCc1nc(N)nc(O)c1C
Temperature: 20 °C
Yield: 26.6 %

Procedure:
Ethyl 2-methyl-3-oxo4-methoxybutyrate(10.5 g, 60 mmol) was added slowly to a suspension of sodium methoxide (6.5 g, 120 mmol) in dimethylformamide(10 ml) while maintaining the reaction temperature under 20° C. A solution of guanidine(5.7 g, 60 mmol) in ethanol was added to a reaction mixture, which was then refluxed for 5 hours, cooled to a room temperature, and neutralized with conc. sulfuric acid. The resulting solid was filtered and dried to give 2.7 g of the titled compound.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 3 °C
Reaction time: 1 h

Procedure:
2.00 g (10.74 mmol) tert-butyl 1-piperazinecarboxylate, 1.30 g (12.89 mmol, 1.2 eq.) triethylamine were dissolved into 25 ml dichloromethan under argon gas. After cooling to 3° C., 1.33 g (11.81 mmol, 1.1 eq.) chloroacetyl chloride was diluted with 5 ml dichloromethane and added dropwise slowly into reaction solution. After stirring at 3° C. for 1 hour, 20 ml purified water was added, organic layer was separated and aqueous layer was extracted once with 40 ml dichloromethane again. Organic layer was collected, dried with magnesium sulfate and concentrated with decompression. Purifying residues by chromatography using silicagel, 2.00 g (71%) target compound as yellow syrup was yielded.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C>[O:16]=[C:7]1[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5](=[O:22])[C:4]2[C:9](=[CH:10][C:11]([C:12]([F:13])([F:15])[F:14])=[C:2]([N:1]3[CH:25]=[CH:29][CH:28]=[CH:27]3)[CH:3]=2)[NH:8]1
Reactant: COC1CCC(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc2c1=O
Yield: 59 %

Procedure:
The solution of 80 mg (0.236 mmol) ) N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 0.092 ml (0.709 mmol) 2,5-dimethoxy-tetrahydrofuran in 1.5 ml acetic acid is refluxed for 2 hours. After rotavapor evaporation of the solvent the residue is purified by reversed phase chromatography (C18) with an acetonitril-water gradient and the product is lyophilized to give 54 mg (59%) of N-(2,4-dioxo-6-pyrrol-1-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide as a brown solid. MS (ES+): m/e =389 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[S-:11][C:12]#[N:13].[Na+].BrBr.O>C(O)(=O)C>[S:11]1[C:3]2[C:4]3[CH:5]=[N:6][NH:7][C:8]=3[CH:9]=[CH:10][C:2]=2[N:1]=[C:12]1[NH2:13]
Reactant: N#C[S-]
Reactant: Nc1ccc2[nH]ncc2c1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc3[nH]ncc3c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
2.0 g (15 mmol) of 5-aminoindazole and 4.9 g (60.5 mmol) of sodium thiocyanate were suspended in 10 ml of acetic acid, and 2.4 g (15 mmol) of bromine was added dropwise to the suspension under ice-cooling. The reaction mixture was allowed to warm to room temperature, and it was stirred overnight. The reaction mixture was poured into water, and the resulting crystals were collected by filtration to give 3.1 g of 6H-pyrazolo[4′,3′:3,4]benzo[1,2-d]thiazol-2-ylamine.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH2:6])[CH2:4][OH:5].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:6][CH:3]([CH2:4][OH:5])[CH2:2][OH:1])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NC(CO)CO
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NC(CO)CO)n4)cc3)cc12

Procedure:
Using 2-hydroxy-1-hydroxymethyl-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 457 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:5]=2[N:6]=1.O.[NH2:18]N.O.C(O)(=O)C>C(OCCO)C>[NH:1]([C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:5]=2[N:6]=1)[NH2:18]
Reactant: NN
Reactant: Nc1nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2s1
Solvent: CCOCCO
Solvent: O
Solvent: CC(=O)O
Product: NNc1nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.0 g of amino-4,6-dinitrobenzthiazole are heated to boiling for 1 hour in 200 ml of 2-ethoxyethanol with 20 ml of hydrazine hydrate (100% purity). After cooling to room temperature, the reaction mixture is poured into a mixture of 750 ml of water and 20 ml of glacial acetic acid, stirred for 1 hour, filtered off under suction, washed with water and dried. 21.0 g of 2-hydrazino-4,6-dinitrobenzthiazole are obtained. Melting point 210°-214° C. (decomposition). After recrystallization from 2-methoxyethanol. Melting point 216°-217° C. (decomposition).
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:1]([O:5][NH:6][C:7]([C@H:9]1[CH2:14][N:13]([C:45]([NH:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:19][CH2:20][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)(=[O:17])=[O:16])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ONC(=O)[C@H]1CNCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCN(S(=O)(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)[C@@H](C(=O)NOC(C)(C)C)C1
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide [prepared as described in Example 15, above] (600 mg, 1.23 mmol) in methylene chloride (8 ml) was added triethylamine (0.15 ml, 1.1 mmol) and tert-butyl-isocyanate (0.15 ml, 1.33 mmol). The reaction was stirred for 4 h, concentrated in vacuo, and the residue was chromatographed (SiO2, PTLC, 50% ethyl acetate/hexanes) to give N-tertbutoxy-4-tert-butylaminocarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (75%) as a clear oil.
Reaction SMILES: C1(N2C3C(O[C@@H]([C@H]4CNC(=O)C4)C)=NC(C4C=CC(N5CCN(S(C)(=O)=O)CC5)=CC=4)=CC=3N=C2)CC1.[CH:38]1([N:41]2[C:45]3[C:46]([O:62][C@@H:63]([C@H:65]4[CH2:69][NH:68][C:67](=[O:70])[CH2:66]4)[CH3:64])=[N:47][C:48]([C:50]4[CH:55]=[CH:54][C:53]([N:56]5[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]5)=[CH:52][CH:51]=4)=[CH:49][C:44]=3[N:43]=[CH:42]2)[CH2:40][CH2:39]1.[CH3:71][CH:72]([S:74](Cl)(=[O:76])=[O:75])[CH3:73]>>[CH:38]1([N:41]2[C:45]3[C:46]([O:62][C@@H:63]([C@H:65]4[CH2:69][NH:68][C:67](=[O:70])[CH2:66]4)[CH3:64])=[N:47][C:48]([C:50]4[CH:55]=[CH:54][C:53]([N:56]5[CH2:61][CH2:60][N:59]([S:74]([CH:72]([CH3:73])[CH3:71])(=[O:76])=[O:75])[CH2:58][CH2:57]5)=[CH:52][CH:51]=4)=[CH:49][C:44]=3[N:43]=[CH:42]2)[CH2:39][CH2:40]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: CC(C)S(=O)(=O)N1CCN(c2ccc(-c3cc4ncn(C5CC5)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Yield: 15 %

Procedure:
Following the procedure described for intermediate 3.45, starting from (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (90 mg, 0.2 mmol) and propane-2-sulfonyl chloride (0.02 ml, 0.22 mmol) to provide 16.6 mg of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(isopropylsulfonyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:14]=2)[C:9](F)=[N:10][CH:11]=1.[F:39][C:40]1[CH:41]=[C:42]([NH2:48])[CH:43]=[N:44][C:45]=1[O:46][CH3:47].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1.O.C(Cl)Cl.CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:15]2[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]3[C:9]([NH:48][C:42]4[CH:43]=[N:44][C:45]([O:46][CH3:47])=[C:40]([F:39])[CH:41]=4)=[N:10][CH:11]=[C:6]([CH:7]=3)[CH:2]=[O:1])[N:14]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4OCCO4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
4-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.688 g, 3.262 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.477 g, 3.36 mmol) were dissolved in THF (28 mL) and the reaction flask was cooled in an ice water bath under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 9.5 mL, 9.5 mmol) was added, and the reaction was stirred under nitrogen for min. Then, aqueous HCl (5.0 M, 4.5 mL, 22.50 mmol) and MeOH (5.8 mL) were added, and the reaction was warmed to room temperature and stirred. After 10 min, the reaction was treated with water (20 mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum. LCMS showed mostly product, but some unhydrolyzed acetonide was also present. The material was dissolved in THF (20 mL) and MeOH (4.0 mL) and aqueous HCl (5.0 M, 2.0 mL, 10 mmol) was added, and the solution was stirred at room temperature. After 25 min, the reaction was diluted with water (20 mL) and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum overnight to give 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (1.098 g). 1H NMR (CDCl3, 400 MHz) δ 12.58 (s, 1H), 9.92 (s, 1H), 9.25 (d, J=2.35 Hz, 1H), 8.75 (d, J=2.15 Hz, 1H), 8.03-7.97 (m, 2H), 7.21 (dd, J=15.06 Hz, 8.41 Hz, 4H), 6.87 (dd, J=11.15 Hz, 8.61 Hz, 4H), 4.89 (s, 2H), 4.85 (s, 2H), 4.04 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.61 (s, 3H). m/z (ESI, pos. ion) 596 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N:15]1([CH2:14][CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C:7]2=[O:20])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCC1)c1cccs1
Reaction time: 64 h

Procedure:
A solution of 6-amino-1-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.053 g, 0.194 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.110 g, 0.386 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1:10-9). The product was dried under high vacuum. Yield: 31 mg of yellow solid (42%). 1H NMR (CDCl3) δ: 7.44 (d, J=5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.84 (d, J=4.2 Hz, 1H), 4.91 (br s, 2H), 4.05-4.00 (m, 2H), 2.89-2.85 (m, 2H), 2.70-2.64 (m, 8H), 2.02-1.97 (m, 2H), 1.90-1.82 (m, 4H). MS (ESI): 383.2 (M+1). ESI-HRMS calculated for C21H27N4SO2 (MH+): 383.1900, Observed: 383.1895.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.C(OCC)(=O)C>[C:34]([NH:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:36])[CH3:35]
Reactant: Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)c([N+](=O)[O-])c2s1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{3-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (1.2 g, 3.0 mmol) in tetrahydrofuran (20 mL) were added pyridine (2.4 mL, 30 mmol) and acetyl chloride (340 μL, 4.8 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (200 mL), washed successively with water (100 mL), 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound as a yellow powder. This was directly used for the next reaction without further purification.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[C:21][CH2:22][CH2:23]O)[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CN(S(F)(F)[F:31])C.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[C:21][CH2:22][CH2:23][F:31])[CH:14]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CN(C)S(F)(F)F
Reactant: O=C(C(=O)c1ccc(F)c(C#CCCO)c1)c1ccc(OC(F)F)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C(=O)c1ccc(F)c(C#CCCF)c1)c1ccc(OC(F)F)cc1
Temperature: -78 °C

Procedure:
In a 100 mL round bottom dissolve 1-(4-Difluoromethoxy-phenyl)-2-[4-fluoro-3-(4-hydroxy-but-1-ynyl)-phenyl]-ethane-1,2-dione (0.670 g, 1.85 mmol) was dissolved in dichloromethane (40 mL) and chilled to −78° C. Add (Dimethylamino)sulfur trifluoride (MeDAST; 2.99 g, 22.4 mmol) was introduced via syringe injection. After 30 minutes dry-ice bath was removed. After 2 hours at ambient temperature the crude reaction was carefully poured into a 500 mL beaker containing 200 cc ice-chips and sodium bicarbonate. An attempted diethyl ether extraction with diethyl ether resulted in emulsion. Sodium chloride was added to break emulsion. Organic layer was concentrated to a residue, and loaded directly on top of an 80 gm chromatography column. Purification [YAMAZEN W-Prep 2XY using automatic gradient elution: 3% EtOAc/hexanes (hold 4 min) to 24% EtOAc (in 12 min), hold 8 minutes] afforded oil that begins to solidify as a wax 360 mg (53%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].C(O)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CO
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-dichloro-6-nitrobenzaldehyde (7.62 g, 34.9 mmol) in tetrahydrofuran (75 mL) was added sodium borohydride (1.31 g, 34.9 mmol) followed by ethanol (1.75 mL), and the mixture was stirred for 1.5 hours. Saturated aqueous ammonium chloride (75 mL) was added, and the solution was extracted three times with EtOAc. The combined organic layers were dried (MgSO4) and then concentrated to give 2,3-dichloro-6-nitrobenzyl alcohol, as an oil which crystallised, 7.62 g (98%).