Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:22]NC.C(Cl)Cl.C=O>C(O)(C)(C)C>[Br:1][C@H:2]1[C:19](=[O:20])[N:4]2[C:5]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:22])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CNC
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C=C1C(C)=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Yield: 5.6 %

Procedure:
A mixture of t-butyl 7α-bromo-3-methyl-3-cephem -4-carboxylate 1,1-dioxide (700 mg, 1.9 mmol), dimethylamine hydrochloride (460 mg, 5.7 mmol), methylene chloride (3 ml) and t-butyl alcohol (50 ml), formaldehyde (0.57 g, 37% w/v) was heated to reflux at 80°-90° C. for 20 hours. t-Butyl alcohol was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, brine, dried and concentrated to give 200 mg of crude product which was purified over silica column using methylene chloride as eluant to give 40 mg of pure t-butyl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide.
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]3[CH:35]=[CH:34][C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:46][C@@H:45]6[C@@H:43]([CH2:44]6)[N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=4)=[CH:32][CH:31]=3)=[CH:18][N:19]=2)[CH2:13][C@@H:12]2[C@H:10]1[CH2:11]2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C@@H:10]12[CH2:11][C@@H:12]1[CH2:13][C@@H:14]([C:15]1[NH:19][CH:18]=[C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]3[CH:31]=[CH:32][C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:46][C@@H:45]6[C@@H:43]([CH2:44]6)[NH:42]5)=[N:38][CH:37]=4)=[CH:34][CH:35]=3)[N:16]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3cccc4c(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)cccc34)cc2)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)c2cccc(-c3ccc(-c4cnc([C@@H]5C[C@H]6C[C@H]6N5)[nH]4)cc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 118.1 %

Procedure:
4M HCl (0.757 mL, 3.03 mmol) in dioxane was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-(4-(5-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (141 mg, 0.202 mmol) in dioxane (3.0 mL) and the reaction was stirred at rt for 6 h. The solids were washed down the sides of the vial with MeOH and the reaction was concentrated under a stream nitrogen to yield an HCl salt of (1R,3S,5R)-3-(5-(4-(5-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-1-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (119 mg) as a yellow solid. LC-MS retention time 2.333 min; m/z 499.57 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.15 (d, J=8.3 Hz, 1H), 8.03-8.08 (m, 2H), 8.01 (d, J=8.0 Hz, 2H), 7.95 (s, 1H), 7.77 (d, J=6.5 Hz, 1H), 7.68-7.74 (m, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.57-7.64 (m, 2H), 5.03 (t, J=9.4 Hz, 1H), 4.97 (dd, J=10.8, 8.0 Hz, 1H), 3.57-3.66 (m, 2H), 2.76-2.89 (m, 4H), 2.11-2.21 (m, 2H), 1.27-1.34 (m, J=7.7, 5.1, 5.1, 2.6 Hz, 2H), 1.05-1.14 (m, 2H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]1([NH:11][C:12]2[C:17]([CH:18]=[N:19][OH:20])=[CH:16][N:15]=[C:14]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:13]=23)[CH2:10][CH2:9]1.Cl[O-].[Na+]>O1CCCC1>[CH:8]1([NH:11][C:12]2[C:17]([C:18]3[CH2:3][C:2]([CH3:4])([C:1]([O:6][CH3:7])=[O:5])[O:20][N:19]=3)=[CH:16][N:15]=[C:14]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:13]=23)[CH2:9][CH2:10]1
Reactant: CCn1ncc2c(NC3CC3)c(C=NO)cnc21
Reactant: C=C(C)C(=O)OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CC3)c(C3=NOC(C)(C(=O)OC)C3)cnc21
Temperature: 25 °C

Procedure:
Methyl methacrylate (0.3 ml, 0.0028 mole) was added to 4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (70 mg, 0.00028 mol) in tetrahydrofuran. The reaction mixture was stirred at room temperature. Sodium hypochlorite (2 ml) was added slowly to the mixture thus obtained over a period of about 5 minutes and the reaction mixture was allowed to stir at room temperature for about 4 hours. Tetrahydrofuran was evaporated and the organic layer was extracted with ethyl acetate. It was concentrated and purified by column chromatography to yield the title compound. Yield: 50 mg (51%). m/z: (M++1) 344.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C@H:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)[C:14]([OH:16])=[O:15])[C:10]1=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C@H:13]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C:14]([OH:16])=[O:15])[C:10]1=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN([C@@H](C(=O)O)c2ccc(OC(=O)OC(C)(C)C)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CN([C@@H](C(=O)O)c2ccc(O)cc2)C1=O
Yield: 82.1 %

Procedure:
A suspension of 9 g (21 mmols) of (3S)-3-tert.-butoxycarbonylamino-(αR)-α-(4-tert.-butoxycarbonyloxyphenyl)-2-oxo-1-azetidineacetic acid and 2.23 g (21 mmols) of Na2CO3 in 60 ml of H2O is warmed at 60° for 2 hours (pH 9). After 2 hours it is filtered and the pH of the clear colourless solution is adjusted to 2 with 2 N HCl. The precipitate is filtered off, washed with water and ethyl acetate and recrystallised from ethyl acetate and methanol. 5.8 g (~82%) of (3S)-3-(tert.-butoxycarbonylamino)-(αR)-α-(4-hydroxyphenyl)-2-oxo-1-azetidineacetic acid are obtained. Melting point: decomposition above 201°.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Cu])#[N:20].CN(C)C=O>O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([C:19]#[N:20])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)c1nc(C#N)c2sccc2c1O
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43a, 165 mg, 0.5 mmol), CuCN (91 mg, 1 mmol), and dimethylformamide (2 ml) was heated in a microwave oven at 160° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with ethyl acetate (1×60 ml). The resulting mixture was filtered through a pad of celite. The organic phase was washed with water (2×25 ml), dried over MgSO4, and concentrated in vacuo to give the title compound as tan solid (72 mg); MS-(−)-ion: MS-(−)-ion: M−1=275.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:24]([OH:26])=[O:25])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(=O)CC>[CH3:37][C:36]([CH3:39])([CH3:38])[C:35](=[O:40])[CH2:34][O:25][C:24]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:12]1)=[O:26]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCC(=O)C(C)(C)C)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3-benzyl ester (2.85 g 7.85 mmol), potassium carbonate (1.4 g 10 mmol) and bromopinacolone (1.73 mL 17 mmol) in butan-2-one is stirred at room temperature for 6 h. The mixture is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. After purification by column chromatography, the product is crystallized in heptane to give piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester melting at 60° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:12].[C:13]([O:17][C:18]([N-:20][S:21](N1C=CC(=[N+](C)C)C=C1)(=[O:23])=[O:22])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CCOC(C)=O.Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:12][S:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])(=[O:22])=[O:23]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: NC1CCc2c(F)ccc(F)c21
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NS(=O)(=O)NC1CCc2c(F)ccc(F)c21
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a solution of 4,7-difluoro-2,3-dihydro-1H-inden-1-amine (CAS No. 625471-13-8, 1.19 g, 11.2 mmol) in DCM (50 mL) were added [(tert-Butoxy)carbonyl]{[4-(dimethyliminio)pyridin-1(4H)-yl]sulfonyl}amide (3.70 g, 12.3 mmol) and TEA (4.66 mL, 33.5 mmol) at room temperature. The resulting solution was stirred for 75 hours at room temperature. The reaction mixture was diluted with AcOEt and 1N HCl and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to afford the title compound (3.82 g, 11.0 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].CC(C)([O-])C.[K+].[Br:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1F.[Cl-].[Na+]>CS(C)=O.O>[Br:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: O=C1NCCCN1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1NCCCN1c1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
910 mg (9.09 mmol) of tetrahydropyrimidinone in 39 ml of DMSO are admixed at RT with 1.53 g (13.6 mmol) of potassium tert-butoxide, and the mixture is stirred at room temperature for 30 min. 2.00 g (9.09 mmol) of 2-bromo-1-fluoro-4-nitrobenzene are added and the mixture is stirred at 60° C. After 18 h, it is cooled and added to 600 ml of water and 160 ml of saturated aqueous sodium chloride solution. It is extracted three times with 300 ml each time of ethyl acetate, and the combined organic phases are dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure and the residue is purified by chromatography on silica gel (60:1 dichloromethane/ethanol). This affords 481 mg (17% of theory) of the desired compound.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].BrCCCCCCCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.O=[CH:69][CH2:70][CH2:71][CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74]>CCOCC.CCCCCC.O.C1(C)C(C)=CC=CC=1>[C:73]([O:75][CH2:76][CH3:77])(=[O:74])[CH2:72][CH2:71][CH2:70]/[CH:69]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCC=O
Agent: CCCCCCCCCCCBr
Agent: [Br-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCC/C=C\CCCC(=O)OCC
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
Undecyltriphenylphosphonium bromide (16.3 g, prepared by heating 1-bromoundecane and triphenylphosphine together in refluxing xylene) is suspended in dry ether (400 ml) and the mixture is stirred under nitrogen whilst 1.7 M butyllithium in hexane (47.5 ml) is added from a syringe. The resulting bright red solution is cooled to 10° C. and treated dropwise with ethyl 5-oxopentanoate (7.25 g) in dry ether (50 ml). After 10 minutes, water (200 ml) is added and when the solid product has dissolved the ether layer is separated and the aqueous layer is washed with ether (3×100 ml). The combined ethereal solutions are dried over magnesium sulphate and the ether is evaporated. The residue is shaken with hexane (200 ml), and the mixture is cooled and filtered. The filtrate is concentrated to a volume of 100 ml and then cooled to allow crystallisation of the triphenylphosphine oxide. When this is complete, the mixture is filtered and the filtrate is evaporated to yield ethyl (Z)-hexadec-5-enoate in crude form as a yellow oil (10.1 g).
Reaction SMILES: Cl.[CH2:2]([O:6][P:7]([O-:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH3:5].[CH2:14]([C:18]([CH3:20])=[O:19])[CH:15]([CH3:17])[CH3:16]>C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-]>[CH2:9]([O:8][P:7]([C:18]([OH:19])([CH3:20])[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:13])[O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)CC(C)C
Reactant: CCCCOP([O-])OCCCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CCCCOP(=O)(OCCCC)C(C)(O)CC(C)C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Into a two-liter four-necked flask provided with a stirrer, a thermometer, dropping device, a hydrochloric-acid-recovering device and a condenser, 213.4 g (1.1 moles) of dibutylphosphite, 5.6 g (0.06 moles) of triethylamine and 1.05 g (0.011 moles) of magnesium chloride were fed. While stirring the resulting mixed solution at 25° C., 120.0 g (1.2 moles) of methyl isobutyl ketone (MIBK) was added thereto in 1 hour. The resulting mixed solution was further stirred for 1 hour at the same temperature (25° C.) to complete the reaction. Thereafter, the mixed solution was washed to remove the low-boiling point portions, as in (synthesis of raw material 2) of Example 1, and thus, the triethylamine and the magnesium chloride was removed from the mixed solution, to obtain 298.8 g of dibutyl(1-hydroxy-1,3-dimethylbutyl)phosphonate (raw material 3).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.[ClH:6].[NH2:7][CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]>>[ClH:6].[NH2:7][CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([O:14][CH2:4][CH2:3][O:2][CH3:1])=[O:13]
Reactant: COCCO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: COCCOC(=O)CCC(=O)CN
Reaction time: 1 h

Procedure:
From 2-methoxyethanol (5.0 g; 66 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 1 h. The yield was 1.25 g (93%) of yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:17][C@@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([NH:17][C@@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[N:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Nc1cc(C(=O)OC(C)(C)C)nc(Cl)n1
Temperature: 50 °C
Yield: 88.7 %

Procedure:
To a mixture of tert-butyl 2,6-dichloropyrimidine-4-carboxylate (0.310 g, 1.24 mmol) in acetonitrile (5 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (0.177 g, 1.27 mmol) and iPr2NEt (0.48 mL, 2.8 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-tert-butyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a colorless glass (0.347 g, 1.10 mmol, 89% yield). 1H NMR (400 MHz, DMSO-d6): 8.70 (1H, d, J=6.8 Hz), 7.12 (1H, s), 4.56-4.47 (1H, m), 3.65 (3H, s), 1.53 (9H, s), 1.39 (3H, d, J=7.2 Hz). LC/MS: m/z=316.2 [M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[C:15](=[O:21])[CH:16]=[CH:17][C:18](=O)[CH:19]=1.C(Cl)Cl>CCO>[OH:21][C:15]1[C:14]([C:13]([F:12])([F:22])[F:23])=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:1][C:2]([CH3:11])=[C:3]2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=C1C=CC(=O)C(C(F)(F)F)=C1
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCO
Product: Cc1[nH]c2ccc(O)c(C(F)(F)F)c2c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 66 %

Procedure:
A stirred solution of 1,1-dimethylethyl (2Z)-3-amino-2-butenoate (47.6 g, 0.3 mol) in EtOH (100 mL) was treated dropwise at ambient temperature with a 1.2 M solution of 2-(trifluoromethyl)-2,5-cyclohexadiene-1,4-dione in CH2Cl2 (300 mL, 0.35 mol) (internal temperature rose to +35° C. during the addition). The reaction was stirred 1 h and concentrated at reduced pressure. Stirring the resulting material with CHCl3 at ice-bath temperature afforded 1,1-dimethylethyl 5-hydroxy-2-methyl-4-(trifluoromethyl)-1H-indole-3-carboxylate as an off-white solid which was collected by filtration (62 g, 66% yield): 1H NMR (DMSO-d6) δ 11.55 (s, 1H), 9.68 (bs, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 2.37 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:6][CH:5]([O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11]N=[CH:13]3)[CH2:4]1.N1CC(OC2C=CC=C3C=2C=CN=C3C(C2C=CC=CC=2)C2C=CC=CC=2)C1>>[ClH:1].[Cl:1][C:17]1[C:8]([O:7][CH:5]2[CH2:6][NH:3][CH2:4]2)=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:11][CH2:10]2
Reactant: c1cc(OC2CNC2)c2ccncc2c1
Agent: Cl
Agent: c1ccc(C(c2ccccc2)c2nccc3c(OC4CNC4)cccc23)cc1
Product: Clc1ccc2c(c1OC1CNC1)CCC2

Procedure:
5-(3-Azetidinyloxy)-isoquinoline dihydrochloride, mp 198° C. starting from 5-(3-azetidinyloxy)-1-(diphenylmethyl)-isoquinoline.
Reaction SMILES: [CH:1]1([CH:4]([NH:8][C:9]([NH:11][CH2:12][CH2:13]Cl)=[S:10])[CH:5]2[CH2:7][CH2:6]2)[CH2:3][CH2:2]1>O>[CH:1]1([CH:4]([NH:8][C:9]2[S:10][CH2:13][CH2:12][N:11]=2)[CH:5]2[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: S=C(NCCCl)NC(C1CC1)C1CC1
Solvent: O
Product: C1CSC(NC(C2CC2)C2CC2)=N1

Procedure:
The raw N-(1,1-dicyclopropylmethyl) N'-(βchloroethyl) thiourea obtained by step (a) is suspended in 100 ml of water and dissolved by warming. After complete solution, the aqueous phase is extracted with ether; the organic phase is discarded. The aqueous solution is made alkaline by adding an excess of 30% soda. An oily fraction separates which is then extracted with ether. The organic solution is washed with water, dried on sodium sulphate, filtered and evaporated to dryness. The cristallized residue is purified by dissolving it in the minimum amount of hot cyclohexane. By standing the solution in a cool place, 6 g of 2-(dicyclopropylmethylamino) thiazoline melting at 127°-128° C. (with decomposition) are recovered.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[Cl:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@@H:19]2[CH3:31])=[N:14][CH:15]=[CH:16][N:17]=1.Cl>>[ClH:11].[CH3:31][C@H:19]1[CH2:20][NH:21][CH2:22][CH2:23][N:18]1[C:13]1[C:12]([O:10][CH2:9][CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:17][CH:16]=[CH:15][N:14]=1
Reactant: OCCOc1cccnc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Agent: Cl
Product: C[C@H]1CNCCN1c1nccnc1OCCOc1cccnc1
Yield: 58 %

Procedure:
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and 3-chloro-2-[4-tert-butoxycarbonyl-(2S)-methyl-1-piperazinyl]pyrazine (prepared according to the procedure of Example 172, Step 2, with the exception that (2S)-methylpiperazine was substituted for (2R)-methylpiperazine). MS m/z 316 (M+H)+. Yield 58%; mp 170-172° C. Anal. (C16H21N5O2.1.45 HCl) C, H, N.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[CH2:8])[S:6][C:5](=[N:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH:26](OCC)=[O:27].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C:7](=[CH2:8])[S:6][C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[C:4]([CH:26]=[O:27])[CH2:3]1
Reactant: CCOC=O
Reactant: C=C1SC(=Nc2ccc(C)cc2)CCC1(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1SC(Nc2ccc(C)cc2)=C(C=O)CC1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
In a dehydrated tetrahydrofuran (15 ml) solution of [5,5-dimethyl-6-methylene-tetrahydro-thiopyran-2-ylidene]-p-tolyl-amine (0.53 g), 2.2 ml of lithium diisopropylamide (1.5 mol/l, tetrahydrofuran/cyclohexane solution) was added dropwise at −78° C. under a nitrogen atmosphere. After stirring at −78° C. for 30 minutes, a tetrahydrofuran (1 ml) solution of ethyl formate (0.24 g) was added dropwise. After raising the temperature to room temperature and further stirring for 1 hour, an aqueous saturated ammonium chloride solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.26 g of the target compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][NH:10][CH3:11].[OH-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:10]([CH3:11])[CH3:9])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCl
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To a solution of 4-chloro-butyryl chloride (1.12 ml, 10.0 mmol) and dimethyl-amine hydrochloride (4.1 g, 50.0 mmol) in THF at 5° C. was added 2M NaOH (30 ml, 60.0 mmol) dropwise over 30 minutes while maintaining reaction temperature between 5-10° C. The reaction was stirred for additional 1.5 h and was concentrated, extracted with EtOAc (×2). The combined organic layer was washed with 1M HCl (×2), brine, dried over Na2SO4, and concentrated in vacuo to yield the title compound as colorless oil (1.5 g, ˜100%). The crude was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][C:18]([O:42][CH3:43])=[C:19]([OH:41])[CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:45][CH2:46][Cl:47].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:47][CH2:46][CH2:45][O:41][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:42][CH3:43])[N:15]=[C:14]([C:4]1[CH:5]=[CH:6][C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[C:2]([F:1])[CH:3]=1)[N:23]=[C:22]2[NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[N:29]=[CH:28]2
Reactant: ClCCBr
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Temperature: 85 °C
Yield: 54.5 %

Procedure:
A mixture of tert-butyl 5-(2-(3-fluoro-4-(phenyl)phenyl)-6-hydroxy-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.61 g, 1.06 mmol), 1-bromo-2-chloro ethane (0.475 g, 3.31 mmol) and K2CO3 (0.533 g, 3.86 mmol) in DMF (5 mL) was heated at 85° C. for 2.5 h. the mixture was allowed to cool to RT upon which, it was poured into water. A solid separated out which was collected via filtration and dried under vacuum. The residue was purified via preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound tert-butyl 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.37 g, 0.578 mmol, 55%). MS 640.3 (M+1 Cl isotope pattern).