Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:26]C)=[C:10]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:25])[CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:26])=[C:10]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:25])[CH:11]=1
Reactant: COc1ccc(Cl)cc1C1C(=O)Nc2cc(C(F)(F)F)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Nc2cc(C(F)(F)F)ccc2C1c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of BBr3 (12 mL, 12 mmol; 1M in CH2Cl2) was added to a stirred cold (-78° C.) solution of (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one (1.37 g, 4 mmol) in anhydrous CH2Cl2 (20 mL). The mixture was allowed to warm to ambient temperature and maintained for 2 hours. The reaction was quenched with saturated NaHCO3 and then acidified with 1N HCl. The organic layer was separated, washed with water, brine and then dried (MgSO4). Evaporation of CH2Cl2 gave an off-white solid which was triturated with warm CH2Cl2 to afford the title compound (1.21 g, 93%): mp 266°-268° C.; IR (KBr, cm-1) 3320, 1690, 1310, 1250, 1160, 1125; 1H NMR (300 MHz, DMSO-d6)δ 4.85 (1 H, s), 6.75 (1 H, d, J=8.6 Hz), 7.04 (1 H, s), 7.11, (1 H, d, J=7.7 Hz), 7.17 (1 H, dd, J=8.6 and 2.6 Hz), 7.22 (1 H, d, J=8.0 Hz), 7.26 (1 H, d, J=2.4 Hz), 9.82 (1 H, s), 10.73 (1 H, s); 13C NMR (75 MHz, DMSO-d6)δ 48.47, 104.94, 116.84. 118.16, 122.27, 124.20, 125.61, 126.06, 128.05, 128.41, 130.76, 134.72, 143.69, 154.26, 176.92. MS m/e 328 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22]([O-:24])C.[Na+].Br[CH:27](OC)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:27][C:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[O:24][CH3:22])=[O:29])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(Br)C(=O)c1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(CC(=O)c3ccccc3OC)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
A mixture of 2 g of compound 1 and 1 eq sodium ethanolate in 30 ml of dimethylformamide was added to a solution of 2 g of ω-bromo-2-methoxyacetophenone in dimethylformamide. After 30 min small portions of additional ω-bromo-2-methoxyacetophenone (total 5 gram) and sodium ethanolate were added during 2 hours. Subsequently the reaction mixture was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (dichloromethane). Crystallized from methanol. M.p. 93°-96° C.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: COC(OC)OC
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)Oc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine, trimethyl orthoformate, p-toluenesulfonic acid monohydrate in toluene was heated at reflux using Dean-Stark apparatus for 24 hours. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated. Anal. For C21H29N30. ¼H2O calc. C, 73.76; H, 8.10; N, 12.29; found: C, 73.22; H, 7.96; N, 12.42.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.B(O)O>>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:27][N:26]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: COc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cn1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2-methoxypyrimidin-5-boronic acid as a boronic acid, 4-(2-methoxy-pyrimidin-5-yl)-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained. This was demethylated in the same manner as Example 1-B-42, to obtain the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH2:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([N:28]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 64.7 %

Procedure:
0.99 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight in 2 g (16 mmol) of dibutylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.82 g (65%) of 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 105°-110°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Product: CC(C)c1ccc(-c2ccnc(Cl)c2)cc1
Yield: 81 %

Procedure:
Part C. A mixture of 4-(4-isopropyl-phenyl)-pyridine-N-oxide (126 mg, 0.59 mmol) and phosphorus oxychloride (5 mL) is heated to reflux for 12 h. The mixture is cooled and evaporated, and the residue is dissolved in water, neutralized with satd. aq. Na2CO3 and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford 2-chloro-4-(4-isopropyl-phenyl)-pyridine (110 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH:13]=[CH2:14]>>[CH2:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=2[CH3:1])=[CH:22][CH:23]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1ccc(C=O)cc1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)cc1

Procedure:
2-Methyl-3-nitroaniline and 4-allyloxybenzaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][O:31][CH3:32]>C(#N)C.CC(OC)(C)C.[I-].[Na+]>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:29][CH2:30][O:31][CH2:32][CH3:22])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CCOCCOc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Yield: 96.2 %

Procedure:
To a suspension of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)-propanoate (4.43 g, 15.00 mmol), K2CO3 (4.15 g, 30.0 mmol) and sodium iodide (112 mg, 750 μmol) in acetonitrile (100 mL) was added 1-bromo-2-methoxyethane (5.64 mL, 60.0 mmol) and the resulting mixture was stirred at reflux for 2 days. The reaction mixture was diluted with TBME and washed with H2O and brine. Combined extracts were dried over MgSO4, filtered and concentrated to provide the title compound as a yellow oil (5.3 g, 95%). TLC (toluene/TBME 2:1) Rf=0.44; tR=1.084 min (UPLC 1); LC-MS: [M+H] 354; Rt 1.02 min; (LCMS method 2); 1H NMR (400 MHz, CDCl3): δ 7.05 (d, 2H), 6.88 (d, 2H), 4.96 (br d, 1H), 4.58 (m, 1H), 4.12 (dd, 2H), 3.76 (dd, 2H), 3.73 (s, 3H), 3.47 (s, 3H), 3.05 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][CH2:6][CH:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@H:16]([N:17]([CH3:27])[C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.C(N=C=O)C1C=CC=CC=1>>[CH3:1][NH:2][C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C@H:16]([N:17]([CH3:27])[C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)=[O:4]
Reactant: CN=C=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(CO)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: O=C=NCc1ccccc1
Product: CNC(=O)OCC1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing substantially the same procedure as described in Example 10, but substituting methyl isocyanate and 17-(hydroxymethyl)-4-methyl-5α-4-azaandrostan-3-one for the benzyl isocyanate and steroid alcohol, respectively, used therein, the title compound was obtained. MS M+ 2 calculated for C22H36N2O3, mw=376.54; observed m/e 378.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=O.C(OP([CH2:54][C:55]#[N:56])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[CH:54][C:55]#[N:56])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc(C)cc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(4-methylphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'-methylbenzophenone (2.3 g, 9 mmol), diethylcyanomethylphosphonate (1.8 mL, 9.9 mmol) and lithium hexamethyldisilazide (10 mL, 9.9 mmol, 1M) with a reaction time of 22 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 1.83 g (73%) of a mixture of the E and Z isomers as a white solid: mp 83.5-86.5° C.; 1H NMR (CDCl3) δ 7.35-7.20 (m, 8H), 7.04-6.81 (m, 6H), 5.62 (s, 1H), 5.59 (s, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H); 13C NMR (CDCl3) δ 162.7, 162.6, 160.0, 150.4, 148.8, 148.5, 140.6, 140.1, 136.3, 134.1, 131.6, 129.5, 129.2, 129.0, 128.5, 123.0, 122.1, 118.4, 118.3, 112.6, 111.1, 110.7, 92.6, 92.4, 55.9, 55.9, 55.8, 21.3, 21.2; Anal. Calcd for C18H17NO2. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.64; H, 5.93; N, 5.01.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.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>[C:11]1([CH3:10])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: Cc1cc(C)c(-c2cccc(CO)n2)c(C)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
(6-Bromopyridin-2-yl)-methanol (4.23 g, 22.5 mmol) was dissolved in 1,2-dimethoxyethane. Tetrakis(triphenylphosphine)palladium(0) (1.30 g, 1.12 mmol) was added and the reaction stirred for 15 minutes at 50° C. Upon cooling, 2,4,6-trimethylbenzeneboronic acid (3.69 g, 22.5 mmol) in 20 mL 1,2-dimethoxyethane was added to the reaction followed by potassium t-butoxide (5.05 g, 50.0 mmol) in 20 mL of t-butanol. The reaction was heated at 90° C. for 0.5 hr. The solution was cooled and filtered through paper. Flash chromatography (30% ethyl acetate/hexanes) gave the desired product as a white solid (3.50 g, 68% yield).
Reaction SMILES: [Br:1][CH:2](Br)[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4].C(N(CC)CC)C.P([O-])(OCC)OCC>O1CCCC1>[Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: O=C(c1ccc2cc(Br)ccc2c1)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reaction time: 8 h
Yield: 97 %

Procedure:
2,2-dibromo-1-(6-bromonaphthalen-2-yl)ethanone (90.0 g, 221 mmol, 1.00) was dissolved in tetrahydrofurane (800 mL), triethylamine (27.67 mL, 199 mmol, 0.9 equiv.) was added followed by diethyl phosphite (45.8 g, 332 mmol, 1.50 equiv.). The reaction mixture was stirred overnight. The reaction mixture was filtrated and the solvent was removed in vacuum. The obtained residue was dissolved in ethyl acetate (1.2 L) and washed with water. The organic layer was separated, dried over sodium sulphate, filtrated and concentrated to yield crude 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (70.3 g). Recrystallization from acetonitrile gave 30 g (first batch) and 6.5 g (second batch) of 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (50%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])=[C:7]([C:11](=[O:22])[C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[N+:19]([O-])=O)[NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:11]([C:7]1[NH:8][C:9]2[C:5]([C:6]=1[NH:23][C:24](=[O:27])[CH2:25][CH3:26])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:22]
Reactant: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2N)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A suspension of 6-chloro-2-(5-chloro-2-nitrobenzoyl)-3-(propionylamino)indole (step 3, 540 mg, 1.33 mmol), ammonium chloride (35.6 mg, 0.665 mmol), iron powder (391 mg, 6.65 mmol), ethanol (20 ml) and water (10 ml) was heated at reflux temperature for 1 h. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated to give a crystalline residue. Purification by flash column chromatography eluting with ethyl acetate/hexane (1:3) afforded 394 mg (79%) of 2-(2-amino-5-chlorobenzoyl)-6-chloro-3-(propionylamino)indole. 1H-NMR (CDCl3) δ: 11.67 (1H, br s), 9.76 (1H, br s), 7.58 (1H, d, J=8.6 Hz), 7.43 (1H, d, J=1.5 Hz), 7.35 (1H, d, J=2.5 Hz), 7.26 (1H, dd, J=2.5, 8.9 Hz), 7.09 (1H, dd, J=1.8, 8.6 Hz), 6.99 (2H, br s), 6.83 (1H, d, J=8.9 Hz), 2.12 (2H, q, J=7.6 Hz), 0.90 (3H, t, J=7.6 Hz).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][C:32]5[N:33]([C:35]([C:38]([F:41])([F:40])[F:39])=[N:36][N:37]=5)[N:34]=4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].CCOCC>[Pd].CCO>[C:5]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH2:30][CH2:31][C:32]5[N:33]([C:35]([C:38]([F:39])([F:40])[F:41])=[N:36][N:37]=5)[N:34]=4)[CH2:27][CH2:28]3)=[CH:21][CH:22]=2)[CH2:12][CH2:13]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 74.6 %

Procedure:
Ammonium formate (99 g, 1568.94 mmol) was added to 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (81.2 g, 156.89 mmol) and 10% palladium on carbon (8.35 g, 7.84 mmol) in EtOH (810 mL) under nitrogen. The resulting mixture was stirred at 70° C. for 6 hours, then ammonium formate (50 g) was added. The mixture was stirred at 70° C. for 2 hours then further portions of 10% palladium on carbon (8.35 g, 7.84 mmol) and ammonium formate (50 g) were added and stirring continued at 70° C. for a further 10 hours. Ammonium formate (50 g) was added and the reaction mixture was stirred at 70° C. for 24 hours then cooled to room temperature. The catalyst was removed by filtration and the reaction charged with further 10% palladium on carbon (8.35 g, 7.84 mmol) and stirred at 70° C. for 16 hours. Further ammonium formate (50 g) was added and the stirring continued for 5 hours. The reaction mixture was cooled to room temperature and a further portion of 10% palladium on carbon (8.35 g, 7.84 mmol) was added. The mixture was heated to 70° C. for a 30 hours, cooled to room temperature and the catalyst removed by filtration and washed with EtOH. The solvent was evaporated and the residue dissolved in DCM (500 mL) and the solution washed with water (500 mL). The aqueous layer was re-extracted with DCM (500 mL), then EtOAc (500 mL×2). The combined extracts were dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford a gum, which was slurried with ether (300 mL) and re-evaporated. Methyl tert-butyl ether (250 mL) was added and the mixture was stirred vigorously for 3 days. The solid was collected by filtration and dried to afford 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (60.8 g, 75%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:20]1[N:25]=[C:24]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:23]=[C:22]([NH:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[N:21]=1.CCOC(C)=O>C1COCC1>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:20]2[N:25]=[C:24]([O:26][CH2:27][C:28]([F:31])([F:29])[F:30])[N:23]=[C:22]([NH:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)[N:21]=2)=[CH:4][CH:5]=1
Reactant: NCc1ccc(O)cc1
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 70 °C
Yield: 75.4 %

Procedure:
4-(aminomethyl)phenol (2.4 g) white solid and iPr2NEt (5.0 g) were added into a solution of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (7.0 g) in THF (150 mL). The mixture was heated at 70° C. for 16 hours. After cooling, the mixture was charged with 250 mL of EtOAc. The resulting solution was washed with water (2×50 mL) and brine (30 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to give a residue which was recrystallized in EtOAc to give 6.54 g of methyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[N:25]=[C:21]([CH3:20])[S:22][CH:23]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 423.01 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:27](I)[CH3:28]>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]([CH2:27][CH3:28])[C:14]([OH:16])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCI
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1cc(OC)c(OC)c(OC)c1
Temperature: -25 °C
Reaction time: 8 h

Procedure:
A 20 L reactor was purged with nitrogen and 3,4,5-trimethoxyphenylacetic acid (1000 g, 4.42 moles) added followed by THF (4000 mL). The suspension was stirred until all acid was dissolved. The resulting solution was then cooled to −25° C. and a 1.0 M THF solution of sodium bis(trimethylsilyl)amide added via cannula over a period of 1 hour in 2 batches of 500 mL each (10.0 moles total) and the mixture stirred for a further 30 minutes. The temperature of the reaction mixture was not allowed to rise above −15° C. during the course of addition. The resulting cream colored colloidal solution was treated at −25° C. with ethyl iodide (424 mL, 5.30 moles) via cannula over a 1 hour period. (A heat kick of 5° C. may be observed for the initial addition of 50 mL of ethyl iodide. If this occurs, the temperature was adjusted to −25° C. and ethyl iodide addition continued.) The solution was allowed to stir at −25° C. for 2 hours as the colloidal solution slowly changes to a homogeneous brown solution. The brown solution was then allowed to warm to room temperature and stirred overnight. After this time the reaction mixture was quenched, with constant stirring, with water (1500 mL) and allowed to stir for a further 1.5 hours. The organic and aqueous layers were allowed to then separate and the organic layer removed and extracted with water (2×1000 mL). All aqueous solutions were combined and acidified to pH 2 by the addition of a 2N HCl solution (3500 mL) and the solution extracted in batches of ˜400 mL with an roughly equivalent volume of EtOAc (6000 mL total). The combined organic extracts were washed with brine (2×1500 mL) and reduced to a volume of 2000 mL on a rotary evaporator at which time a brown crystalline solid began to precipitate. The solution was allowed to cool and the solid material was filtered, washed with a 1:1 EtOAc:hexanes solution, and the cream colored solids left in a vacuum oven at 40° C. overnight for a first crop of product, AP14900, (582.8 g). The filtrate was further evaporated and two additional crops (166.2 and 158.1 g) were obtained (907.05 g total, 80.6%).