Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][C:21]2=[O:30])=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].Cl>C(O)C.O>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=1[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c(C(=O)OCC)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1CCC(=O)O
Temperature: 95 °C
Yield: 99.4 %

Procedure:
A mixture of 4-(2-ethoxycarbonylethyl)-3-methyl-5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (346 mg) and potassium hydroxide (560 mg) in ethanol (5 mL) was heated to 95° C. and then cooled, upon which red crystals formed. The crystals were dissolved in water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 299 mg (100%) of 4-(2-carboxyethyl)-3-methyl-5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid as a brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C1CCCCC1.C(OCC)(=O)C>[Pd].C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]([CH2:7][C:2]([CH3:17])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(C)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(C)(C)Cc1cccc(N)c1
Reaction time: 12 h

Procedure:
At room temperature, 1 g of palladium on carbon (10%) was added to a solution of 12 g (51.42 mmol) of methyl 2,2-dimethyl-3-(3-nitrophenyl)propanoate in 200 ml of ethanol, and the mixture was hydrogenated under atmospheric pressure for 12 hours. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→1:1). This gave 9.2 g (44.39 mmol, 86% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH3:13].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:18])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)Nc1ccccc1C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CCCC(Cl)=Nc1ccccc1C(F)(F)F
Yield: 99.4 %

Procedure:
Using the procedure of Step B of Example 6, 23.1 g of the product of Step A and 22.9 g of phosphorus pentachloride were reacted to form 24.8 g of N-(2-trifluoromethylphenyl)-butanimidoyl chloride as an oil which was used as is for the next step.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42](C(OC(C)(C)C)=O)[C:43]([N:52]3[CH2:55][CH:54]([CH2:56][NH:57]C(OC(C)(C)C)=O)[CH2:53]3)=[N:44]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:57][CH2:56][CH:54]1[CH2:55][N:52]([C:43](=[NH:44])[NH:42][CH2:41][C:39]2[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]3[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]4([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]4)/[C:72]4[N:73]=[C:74]([NH2:77])[S:75][CH:76]=4)[C:29](=[O:30])[N:28]3[S:31]([OH:34])(=[O:33])=[O:32])[N:40]=2)[CH2:53]1
Reactant: CC(C)(C)OC(=O)N=C(N1CC(CNC(=O)OC(C)(C)C)C1)N(Cc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1)N1CC(CN)C1
Yield: 26.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((N,N′-bis(tert-butoxycarbonyl)-3-(((tert-butoxycarbonyl)amino)methyl)azetidine-1-carboximidamido)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (690 mg, 0.57 mmol), DCM (3 mL) and TFA (2.1 mL, 27.4 mmol). The crude residue was purified via reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound (98 mg, 27%). LCMS: Rt=0.32 min, m/z=641.3 (M+1), Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.06 (s, 1H), 7.72-7.54 (m, 3H), 7.18 (s, 2H), 6.74 (s, 1H), 5.25 (dd, J=8.9, 5.5 Hz, 1H), 4.88 (dd, J=14.2, 4.3 Hz, 1H), 4.65 (dd, J=14.2, 7.7 Hz, 1H), 4.53 (ddd, J=7.6, 5.6, 4.4 Hz, 1H), 4.46-4.31 (m, 2H), 4.15 (td, J=8.7, 5.0 Hz, 2H), 3.96-3.81 (m, 2H), 3.11 (d, J=7.3 Hz, 2H assumed; partially obscured by water), 2.91 (p, J=6.8 Hz, 1H), 1.26-1.11 (m, 2H), 1.08-0.95 (m, 2H).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[OH-].[Na+].[OH-].[NH4+:20]>>[NH2:20][C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: [NH4+]
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Yield: 95 %

Procedure:
benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.5 g) was stirred in 200 ml of saturated ammonium hydroxide at 35° C. for 40 h. The reaction mixture was poured into 100 ml of 2 N NaOH, extracted methylene chloride (4×200 ml), dried MgSO4, filtered and concentrated to provide the title compound as an oil (10.15 g, 95%): 1H NMR (300 MHz, CDCl3) δ) 7.34, 5.14, 3.99, 3.78, 3.37, 3.19, 1.77; HRMS (FAB) calcd for C12H16N2O3+H 237.1239, found 237.1244.
Reaction SMILES: CNC(=NS([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(=O)=O)C.[OH-].[Na+].[CH3:21][N:22](C=CC1C=CC([N+]([O-])=O)=CC=1)[C:23](=[NH:30])[C:24]1C=CC=CC=1>CC(C)=O>[CH3:21][N:22]([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[C:23](=[NH:30])[CH3:24]
Reactant: CN(C=Cc1ccc([N+](=O)[O-])cc1)C(=N)c1ccccc1
Reactant: CNC(C)=NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=N)N(C)C=Cc1ccc(Cl)c(Cl)c1

Procedure:
Treating N-methyl-N'-(3,4-dichlorostyrylsulfonyl)acetamidine with aqueous sodium hydroxide in acetone according to the procedure of Example 32 (c) provides N-methyl-N-(3,4-dichlorostyryl)acetamidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(CO)oc23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
1.5 g (3.8 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 10 ml of tetrahydrofuran, and 4.5 ml of diisobutylaluminum hydride (0.94M hexane solution) was dropwise added thereto in a nitrogen stream at 5° C. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.4 g (yield: 90.7%) of the desired product as pale yellow crystals. Melting point: 198-199° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][N:8]=[C:9]([C:35]2[N:36]=[C:37]([NH:40]C=O)[S:38][CH:39]=2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[N:2]1.Cl.CO>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][N:8]=[C:9]([C:35]2[N:36]=[C:37]([NH2:40])[S:38][CH:39]=2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[N:2]1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccon3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccon3)c3csc(N)n3)[C@H]2SC1
Yield: 45.3 %

Procedure:
A mixture of 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g), conc.hydrochloric acid (0.497 g), methanol (15 ml) and tetrahydrofuran (3 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(3-isoxazoly)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.65 g).
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([CH:6]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)[CH:21]=[CH:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=3[O:35][CH3:36])[CH2:16][CH2:15]2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C(Cl)(Cl)Cl.CO>CCOCC>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH:21]=[CH:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=3[O:35][CH3:36])[CH2:18][CH2:19]2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:39][CH:38]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C=CC=CC(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(C=CC=CCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Yield: 95 %

Procedure:
10.6 g (20 mmol) of said 1-(4,4' difluorobenzhydryl)-4-(5-(2,3,4-trimethoxyphenyl)-2,4,-pentadienoyl)piperazine was dissolved in 250 ml of dry ether. After addition of 760 mg (20.1 mmol) of lithium aluminum hydride, the mixture was heated under reflux for 1 hour. The reaction mixture, after addition of saturated aqueous solution of ammonium chloride, was extracted with ether. The organic layer was then washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. There was obtained a residue, which was subjected to column chromatography on silica gel to give 9.8 g (19 mmol) of 1-(4,4'-difluorobenzhydryl)-4-(5-(2,3,4-trimethoxyphenyl)-2,4-pentadienyl)piperazine from eluates of chloroform-methanol (40:1). Spectrophotometric data of the product support the structure (IX). ##STR9##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:13](=[O:15])(=[O:14])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]2([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:13](=[O:15])(=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(Br)s2)CCN(C(=O)OC(C)(C)C)CCS1(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1(c2ccc(Br)s2)CCNCCS1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a solution of tert-butyl 2-[7-(5-bromo-2-thienyl)-4-tert-butoxycarbonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (5.00 g) in ethyl acetate (25 ml) was added 4N hydrochloric acid in ethyl acetate (13 ml) with ice-cooling. After stirring for 4 hours at room temperature, the mixture was poured into saturated aqueous sodium bicarbonate (50 ml). The separated organic layer was washed with brine, dried over sodium sulfate and filtered. The obtained filtrate was concentrated to give tert-butyl 2-[7-(5-bromo-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (3.03 g) as a solid.
Reaction SMILES: [N:1]([C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=O.C(=O)(O)[O-].[Na+].[C:23](O)(=[O:25])[CH3:24]>[Zn]>[C:23]([NH:1][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: O=Nc1c(-c2ccccc2)nn2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Product: CC(=O)Nc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.81 g) and zinc powder (0.95 g) in acetic acid (10 ml) was heated under reflux for 2.5 hours. The reaction mixture was poured onto ice-water (100 ml) and neutralized with saturated aqueous sodium bicarbonate solution. Resultant precipitates were collected by filtration, washed with water, and recrystallized from ethyl acetate to give crystals of 3-acetamido-2-phenylpyrazolo[1,5-a]pyridine (304 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:25])[C:22]#[C:23][CH3:24])[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:34]([F:46])=[CH:33][C:32]=1[N:47]1[C:59](=[O:60])[C:58]2[S:57][C:56]3[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=3[C:50]=2[CH:49]=[N:48]1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:46][C:34]1[CH:33]=[C:32]([N:47]2[C:59](=[O:60])[C:58]3[S:57][C:56]4[CH2:55][CH2:54][CH2:53][CH2:52][C:51]=4[C:50]=3[CH:49]=[N:48]2)[C:31]([CH2:30][O:29][C:26](=[O:28])[CH3:27])=[C:36]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[N:16]=[C:15]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:25])[C:22]#[C:23][CH3:24])[CH:14]=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:35]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: CC#CC(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC#CC(=O)NCCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
A mixture of N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)but-2-ynamide 116a (224 mg, 0.45 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 108c (240 mg, 0.59 mmol), Pd(dppf)Cl2 (90 mg, 0.12 mmol) and K3PO4 (250 mg, 1.18 mmol) in acetonitrile (10 mL) and water (1 mL) was stirred at 90° C. for 3 h under N2. The mixture was filtered and the filtrate was concentrated to give N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]but-2-ynamide 106a (330 mg crude) as a brown solid. ESI-LCMS: m/z=696.8. This material was used for the next step directly
Reaction SMILES: N12CCCN=C1CCCCC2.F[C:13]1[C:31]([I:32])=[C:30]([CH3:33])[CH:29]=[CH:28][C:14]=1[C:15](=[N:26][OH:27])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.O>O1CCCC1>[I:32][C:31]1[C:13]2[O:27][N:26]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:14]=2[CH:28]=[CH:29][C:30]=1[CH3:33]
Reactant: COc1ccc(CNC(=NO)c2ccc(C)c(I)c2F)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COc1ccc(CNc2noc3c(I)c(C)ccc23)cc1
Yield: 38.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.0 mmol) was added dropwise to a solution of 2-fluoro-N′-hydroxy-3-iodo-N-(4-methoxybenzyl)-4-methylbenzimidamide (preparation 23a, 0.80 g, 1.9 mmol) in tetrahydrofuran (10 mL). The mixture was then heated under microwave conditions (“Initiator sixty” from Biotage®) at 150° C. for 4 hours under an argon atmosphere. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (10:1 to 4:1 hexanes/ethyl acetate) to give the title compound (0.29 g, 38%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[S:14]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)(=[O:16])=[O:15])([O-])=O.Cl[Sn]Cl>Cl.CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:11])[F:13])=[CH:6][C:5]=1[S:14]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)(=[O:15])=[O:16]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 74.9 %

Procedure:
In a similar fashion using route 1 general procedure 4, 2-nitro-N-quinolin-8-yl-5-trifluoromethyl-benzenesulfonamide (Intermediate 270) (490 mg, 1.2 mmol), SnCl2 (936 mg, 4.93 mmol), 6N HCl (5 drops) and EtOH (10 ml) gave the title compound (330 mg, 73%) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:13]1CCCC[CH2:14]1.N1C=NC=NC=1>C(O)C>[F:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[F:11])[N:1]=[CH:14][NH:13][C:4]2=[O:5]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: C1CCNCC1
Agent: c1ncncn1
Solvent: CCO
Product: O=c1[nH]cnc2cc(F)c(F)cc12
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 4.81 g (27.8 mmol) of commercially available 2-amino-4, 5-difluorobenzoic acid in 20 ml of ethanol were added 1.92 ml (19.4 mmol) of piperidine and 2.25 g (27.8 mmol) of 1,3,5-triazine, followed by heating under reflux in an atmosphere of argon for 6.5 hours. After the reaction mixture was allowed to cool to room temperature, the solvent was evaporated. To the residue was added water, and the resulting mixture was neutralized with 4 N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give 4.37 g (86%) of 6,7-difluoro-4(3 H)-quinazolone.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[I:10]I>[OH-].[Na+].ClCCl>[I:10][C:6]1[NH:5][C:4]([CH2:3][O:2][CH3:1])=[N:8][C:7]=1[CH3:9]
Reactant: COCc1nc(C)c[nH]1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCc1nc(C)c(I)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2-(methoxymethyl)-4-methyl-1H-imidazole (compound 222.2, 1.9 g, 15.06 mmol) in sodium hydroxide aqueous solution (30 mL, 2M). This was followed by the addition of a solution of iodine (7.7 g, 30.34 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 1 h at room temperature. The aqueous phase was collected and the pH was adjusted to 4 with hydrogen chloride (2M). The reaction mixture was extracted with 4×30 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium sulfite (sat.) and 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 1.2 g (32%) of the title compound as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3][CH:2]=1
Reactant: COC(=O)C=Cc1cncnc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COC(=O)CCc1cncnc1
Temperature: 110 °C
Yield: 30.2 %

Procedure:
To a solution of methyl 3-(5-pyrimidyl)acrylate (85 g) in glacial acetic acid was added 10% palladium on charcoal (11.3 g) and ammonium formate (74.2 g) under argon. The mixture was heated at 110° C. for 20 min, cooled and the solvent removed in vacuo. The resulting oil was dissolved in dichloromethane (1.5 L) and washed with saturated sodium bicarbonate (750 ml). The aqueous layer was extracted with further dichloromethane (200 ml), the organic layers were combined and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave an oil. This was distilled under reduced pressure to give methyl 3-(5-pyrimidyl)propionate (26 g). 1H-NMR (CDCl3) δ 2.69(2H, t), 2.97(2H, t), 3.70(3H, s), 8.65(2H, s) and 9.12(1H, s).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][N:17](C(OC(C)(C)C)=O)[CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:48])[N:36]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2
Reactant: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2ccc(Oc3cc4cnn(C)c4cc3-c3cn[nH]c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a round bottom flask is added tert-butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (1.92 g, 2.94 mmol) and DCM (50 mL) followed by triethylsilane (1.88 mL, 11.77 mmol) and TFA (17.8 mL, 235.35 mmol). The reaction mixture is allowed to stir at RT for 1.5 hours. The solvent is removed and diluted into DCM (150 mL) and washed with saturated aqueous NaHCO3 solution (2×100 mL). The organic solution is dried with Na2SO4, and concentrated under reduced pressure to give a solid material. The solid is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in DCM solution (B), gradient from 100% (A) to 75%(A):25%(B) over 70 min, held at this 75:25 ratio for 15 min to give the title compound as an off-white solid. The solid is dissolved in hot EtOH (50 mL) followed by a portion-wise addition of distilled water (250 mL) causing a white solid to precipitate. The solid is filtered over a Buchner funnel and washed with distilled water (3×15 mL), air dried, and vacuum dried at 60° C. for 15 hours to give the title compound as an off-white solid (1.27 g, 78% yield). MS (m/z): 552.8 (M+H).