Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:8]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[C:9]#[CH:10].[CH2:17]=O.[OH-].[Na+]>O.O1CCOCC1.C(O)(=O)C>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:17][C:10]#[C:9][CH2:8][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:4]1
Reactant: C#CCN1CCCC1=O
Reactant: COC1CCNC1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COC1CCN(CC#CCN2CCCC2=O)C1
Yield: 61 %

Procedure:
A mixture of 365 mg of (racemic)-3-methoxypyrrolidine, 530 mg of N-propargyl-2-pyrrolidinone, 180 mg of paraformaldehyde, 0.6 ml of acetic acid, 20 ml of dioxane and 10 mg of cuprous chloride was stirred at reflux under argon for 1 hour. The reaction was cooled and treated with a mixture of 3 ml of 5N sodium hydroxide and 2 ml of water. The mixture was extracted twice with dichloromethane. The extracts were combined, dried, filtered and concentrated in vacuo to an oil. The oil was purified by chromatography (alumina), giving 520 mg of the desired product as a yellow oil.
Reaction SMILES: [F-].[Cs+].O1CCOCC1.Br[C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1.[CH:19](/B(O)O)=[CH:20]\[CH3:21]>O.CCCCCC>[F:16][C:14]1[CH:15]=[C:10](/[CH:19]=[CH:20]/[CH3:21])[CH:11]=[C:12]([F:18])[C:13]=1[F:17]
Reactant: C/C=C/B(O)O
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: C/C=C/c1cc(F)c(F)c(F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
In nitrogen atmosphere, tetrakistriphenyl-phosphine palladium(0) (4.66 g) and cesium fluoride (21.4 g) were added to a solution mixture of dioxane (95 mL) and water (5 mL) of 1-bromo-3,4,5-trifluorobenzene (8.5 g), trans-1-propen-1-ylboronic acid (4.1 g). The resulting reaction solution was stirred at 80° C. for 5 hr and cooled to room temperature. To the reaction solution, hexane and water were added. The precipitated insoluble matter was removed by filtration, and the organic layer was separated. The obtained organic layer was washed with water, and the insoluble matter was removed by filtration again. The organic layer was separated. The obtained organic layer was washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: hexane) to give 5.83 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc([C@@H]2C[C@H]2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a cooled solution of tert-butyl ((trans)-2-(4-aminophenyl)cyclopropyl)carbamate (1 g, 4.03 mmol) in dichloromethane (5 mL) was added TEA (0.842 mL, 6.04 mmol), acetyl chloride (0.315 mL, 4.43 mmol) and stirred for 2 h at RT. The reaction mixture was diluted with ice cold water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated. The residue was purified using silica gel (100-200 mesh) column chromatography, compound eluted in 2% MeOH in DCM to afford tert-butyl ((trans)-2-(4-acetamidophenyl)cyclopropyl)carbamate (900 mg, 77% yield) as brown solid. LCMS (ES) m/e 289.26 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:44])[C@H:19]([NH:30][C:31](=[O:43])[C:32]([NH:35]C(=O)OC(C)(C)C)([CH3:34])[CH3:33])[CH2:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH:22]=4)[CH2:13]3)[C:11](=[O:45])[N:10]([CH3:46])[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:35][C:32]([CH3:34])([CH3:33])[C:31]([NH:30][C@H:19]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:12]2([C:11](=[O:45])[N:10]([CH3:46])[CH2:9][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:44])=[O:43]
Reactant: CN1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)C(C)(C)N)C2)C1=O

Procedure:
A mixture comprising tert-butyl 1-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (312.3 mg, 0.493 mmol) (step 1) and TFA (0.380 ml, 4.93 mmol) in DCM (3 ml) was stirred at room temperature for 17 hours. TFA (1 mL, 13 mmol) was added to the reaction mixture. After 3 h 45 min the solvent was removed in vacuo to afford a colourless oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].N(OC(C)(C)C)=O.[I:18]I.[O-]S([O-])=O.[Na+].[Na+]>C(#N)C>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([I:18])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: II
Agent: CC(C)(C)ON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc(Br)ccc1I
Reaction time: 1 h
Yield: 65 %

Procedure:
2-amino-5-bromobenzonitrile (100 g, 0.5 mol) was added during 1 hour to tert-butyl nitrite (117 mL, 0.75 mol) and iodine (250 g, 1.1 mol) in dry acetonitrile (600 mL) under nitrogen while maintaining the temperature between 30° C. and 35° C. Stirring was continued for 60 minutes at 23° C. Subsequent addition of saturated aqueous Na2SO3 (2 L) gave precipitate which was collected by filtration, and washed with hexanes to obtain 100 g (65%) of 5-bromo-2-iodobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J=2.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.64 (dd, J=2.4, 8.4 Hz, 1H).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=[CH:10][C:11]=1[Cl:12].[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:7]=1[CH:1]=[CH:2][NH:13]2.[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([CH:1]=[CH:2][NH:13]2)=[CH:10][C:11]=1[Cl:12]
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc2cc[nH]c2cc1Br
Product: Clc1ccc2[nH]ccc2c1Br
Temperature: 25 °C
Yield: 9.7 %
Yield: 7.9 %

Procedure:
A 1.0 M solution of vinylmagnesium bromide in THF (0.13 L, 130 mmol) is added slowly to 10 g (43 mmol) of 3-bromo-4-chloro-nitrobenzene in 140 mL of THF at −40° C. The mixture is stirred at −40 C for an additional hour when aqueous NH4Cl is added. The mixture is allowed to warm to rt, and then is extracted with EtOAc. The extract is washed with brine, dried over MgSO4, filtered, concentrated, and purified twice by chromatography (33% EtOAc in hexanes) to provide 0.95 g (9.7%) of 4-bromo-5-chloro-1H-indole and 0.77 g (7.9%) of 6-bromo-5-chloro-1H-indole. Each of the indole products is separately treated with 1.1 equivalents of Boc2O and 0.2 equivalents of DMAP in MeCN. The mixtures are concentrated and the residues chromatographed (10% EtOAc in hexanes) to provide I-011 (32%) and I-012 (48%).
Reaction SMILES: C[Si](C)(C)CCOC[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.O.[C:17]1(C)[CH:22]=C[C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+].[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:19]([C:18]1[CH:17]=[CH:22][C:36]([C:37]([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[OH:7])=[O:33])=[CH:35][CH:34]=1)[CH3:20]
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCc1ccc(C(=O)c2ccncc2O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Next, a mixture of 4-(4-ethylbenzoyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (3.4 g), p-toluenesulfonic acid monohydrate (3.46 g, 18.2 mmol) and tetrahydrofuran (60 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give the titled compound (1.57 g, 83%).
Reaction SMILES: [OH-:1].[Na+:2].[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:15]([OH:18])([OH:17])=[O:16])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1.CN(C=[O:23])C>O>[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:11]([O-:14])([OH:13])=[O:12])([P:15]([O-:17])([OH:18])=[O:16])[OH:10])[CH:4]=1.[OH2:23].[OH2:1].[OH2:10].[OH2:10].[Na+:2].[Na+:2]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Reactant: CN(C)C=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of sodium hydroxide (0.7 g) in a mixture of water (20% v/v)/DMF (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (10 ml) was added drop-wise to a suspension of Zoledronic acid form XII (4.98 g) in a mixture of water (20% v/v)/DMF (80% v/v, 10 volumes per grams of ZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with DMF (2×10 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 4.8 g (92%) of Zoledronate disodium crystal form XIV (LOD by TGA=1.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[N-:11]=[C:12]=[S:13].[NH4+].[NH2:15][C:16]1[N:20]([CH3:21])[N:19]=[CH:18][C:17]=1[C:22]#[N:23]>CC(C)=O.O>[C:22]([C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[NH:15][C:12]([NH:11][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[S:13])#[N:23]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: [N-]=C=S
Reactant: Cn1ncc(C#N)c1N
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1ncc(C#N)c1NC(=S)NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
6.4 ml (50 mmol) of p-chlorobenzoyl chloride were added to a solution of 4.2 g (55 mmol) of ammonium isothiocyanate in 100 ml of acetone at about 20° C. Stirring was carried out for 30 minutes, after which a solution of 6.1 g (50 mmol) of 5-amino-4-cyano-1-methylpyrazole in 100 ml of acetone was slowly added dropwise at 50° C. This mixture was heated at the boil for 4 hours, cooled to about 25° C. and then diluted with 1000 ml of water. The product was extracted with ethyl acetate. Yield: 65%.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH2:13][CH3:14])[CH2:11][OH:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:15][C:16]1[CH:17]=[C:18]([S:21]([NH2:24])(=[O:23])=[O:22])[S:19][CH:20]=1.NC1SC(S(N)(=O)=O)=CC=1>C(O)C.Cl>[Br:1][C:2]1[C:3]([NH:9][CH:10]([CH2:11][OH:12])[CH2:13][CH3:14])=[N:4][C:5]([NH:15][C:16]2[CH:17]=[C:18]([S:21]([NH2:24])(=[O:23])=[O:22])[S:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1Br
Reactant: Nc1csc(S(N)(=O)=O)c1
Agent: Cl
Agent: Nc1ccc(S(N)(=O)=O)s1
Solvent: CCO
Product: CCC(CO)Nc1nc(Nc2csc(S(N)(=O)=O)c2)ncc1Br
Reaction time: 21 h

Procedure:
530 mg (1.9 mmol) of (R)-2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-butan-1-ol is added to a suspension of 303 mg of a mixture that consists of 4-amino-thiophene-2-sulfonic acid amide and 5-amino-thiophene-2-sulfonic acid amide (ratio: 2:1) in 7 ml of ethanol and 170 μl of concentrated HCl. The reaction mixture is stirred for 21 hours under reflux. After cooling, the batch is purified by chromatography (Flashmaster II, hexane/EE 2:8). The crude product that is obtained is then recrystallized (ethyl acetate/diisopropyl ether). 47 mg (0.11 mmol, 7% of theory) of the product 4-[5-bromo-4-(1-hydroxymethyl-propylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonic acid amide is obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@@H:31]([OH:39])[CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:25][C:23]=2[N:24]=1.C(N(C(C)C)CC)(C)C>C(O)C>[OH:39][C@H:31]([CH2:30][O:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH3:19])=[N:24][C:23]=2[CH:25]=1)[CH2:32][N:33]1[CH2:34][CH2:35][N:36]([CH2:2][C:3]([NH:5][C@@H:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4])[CH2:37][CH2:38]1
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Reactant: CCOC(=O)[C@@H](NC(=O)CCl)c1ccc(F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](NC(=O)CN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1)c1ccc(F)cc1

Procedure:
Ethyl (2S)-2-(2-chloroacetylamino)-2-(4-fluorophenyl)acetate (400 mg, 1.46 mmol), (2S)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol (560 mg, 1.46 mmol), and 1.26 ml diisopropylethylamine (7.3 mmol) was refluxed in ethanol for 24 hours. Solvent was removed under reduced pressure, and the residue purified by Prep TLC, to provide ethyl (2S)-2-(2-{4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol -5-yloxy)propyl]piperazinyl}acetylamino)-2-(4-fluorophenyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([CH2:12][CH3:13])[N:3]=1.CCOC(C)=O>CO.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:12][CH3:13])=[N:5][C:6]=1[Cl:11]
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1nc(Cl)c(N)c(Cl)n1
Yield: 100 %

Procedure:
4,6-Dichloro-5-nitro-2-ethylpyrimidine (185 g, 0.83 mol) was dissolved in methanol (1.5 L) and reduced under 15 p.s.i. H2 in the presence of Raney nickel (30 g) for 5 hr. The mixture was filtered through Celite (washing well with MeOH) and the filtrate was evaporated to dryness to give 159.1 g (0.83 mol, quantitative yield) of the title compound as a chromatographically pure (silica gel plates, developed with EtOAc:hexanes, 3:1) dark liquid which was used directly in the next step.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:8][C:7]=1[F:14]
Reactant: OCc1ccc(C2OCCO2)c(F)c1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(COc2ccccn2)ccc1C1OCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To an N,N-dimethylformamide solution (20 mL) of (4-[1,3]dioxolan-2-yl-3-fluoro-phenyl)-methanol (2.44 g, 12.3 mmol) described in Manufacturing Example 204-1-3 was added sodium hydride (537 mg, 14.8 mmol, 60% in oil), which was cooled to 0° C., after which 2-fluoropyridine (1.27 mL, 14.8 mmol) was added to this suspension, which was stirred for 2 hours at 60° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (2.17 g, 64%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C)C=O>[Si:12]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COC(=O)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5.0 g (32 mmol) of methyl 4-hydroxycyclohexanecarboxylate were initially charged in 100 ml of dimethylformamide. 6.7 g (44 mmol) of tert-butyldimethylsilyl chloride and 4.1 g (60 mmol) of imidazole were then added, and the mixture was stirred at RT for another 14 h. The solvent was removed under reduced pressure and the residue was taken up in 100 ml of methyl tert-butyl ether and 100 ml of saturated aqueous sodium bicarbonate solution. The phases were separated, the organic phase was dried over magnesium sulphate and filtered and the solvent was removed under reduced pressure. Yield: 8.1 g (93% of theory)
Reaction SMILES: CC1(C)[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1.CN([CH:29]=[O:30])C>O1CCCC1>[CH3:7][CH2:6][CH2:5][CH:4]([CH3:9])[CH3:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][C:18]=1[CH:29]=[O:30]
Reactant: OCCc1ccc(F)cc1
Reactant: CN(C)C=O
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(C)C
Product: O=Cc1cc(CCO)ccc1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2,2,6,6-Tetramethylpiperidine (3.0 g) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexanes, 13 mL) in dry tetrahydrofuran (12 mL) at −78° C. After 10 min, 2-(4-fluorophenyl)ethanol (1.00 g) was added dropwise. The reaction mixture was stirred at −78° C. for 5 h and then dry DMF (3.18 mL) was added dropwise over 5 min. The cooling bath was removed and the reaction mixture allowed to warm to room temperature overnight. Ethyl acetate and aqueous HCl (2M) were added and the solution separated. The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate:isohexane, 1:1 to give the subtitled compound as an oil. Yield 0.43 g.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[H][H].C(N(CC)CC)C.[CH3:35][OH:36]>[Pd]>[O:36]=[C:35]1[NH:1][C:4]2[N:5]=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][CH2:11][N:12]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2cccnc2[N+](=O)[O-])CC1
Reactant: CO
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cccnc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
tert-Butyl 4-(2-(2-nitropyridin-3-yl)ethylamino)piperidine-1-carboxylate (0.561 g, 1.601 mmol) was dissolved in methanol (60 mL). A catalytic amount of 10% palladium on carbon was added to the mixture. Reaction vessel was charged with 2 atm hydrogen gas. Reaction shook at room temperature for 16 hours. The reaction mixture was filtered through a pad of celite twice. Filtrate was concentrated in vacuo. Residue was dissolved in acetonitrile (100 mL). Triethylamine (0.672 ml, 4.82 mmol) was added to the mixture followed by N,N′-carbonyldiimidazole (0.32 g, 1.97 mmol. 1.2 equiv). After 1.5 hours more N,N′-carbonyldiimidazole (0.32 g, 1.97 mmol, 1.2 equiv) was added. Reaction stirred at room temperature for 16 hours. Additional N,N′-carbonyldiimidazole (0.32 g, 1.97 mmol) and triethylamine (0.672 ml, 4.82 mmol) were added and the clear solution was stirred at room temperature for 20 hours. Additional N,N′-carbonyldiimidazole (0.32 g, 1.97 mmol) and triethylamine (350 μL, 251 mmol) were added to the reaction mixture. The clear solution was stirred at room temperature for 68 hours. All solvents were removed by roto-vap. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound as off white solid in 92% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.20 (d, J=4.88 Hz, 1 H) 7.92 (s, 1 H) 7.33 (d, J=7.63 Hz, 1 H) 6.82 (dd, J=7.48, 4.73 Hz, 1 H) 4.35-4.50 (m, 1 H) 4.19 (bs, 2 H) 3.37-3.48 (m, 2 H) 2.87-2.92 (m, 2 H) 2.71-2.83 (m, 2 H) 1.72 (d, J=10.38 Hz, 2 H) 1.50-1.63 (m, 2 H) 1.44 (s, 9 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][CH:20]([CH3:28])[C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])(=[O:3])[NH2:2].[OH-].[K+]>CO.O>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][CH:20]([CH3:28])[C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])(=[O:3])[NH2:2]
Reactant: COC(=O)C(C)(C)C(C)Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)C(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Methyl 3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylbutanoate (0.2 g, 0.526 mmol) was taken in a mixture of MeOH (30 mL) and water (3 mL). Potassium hydroxide (0.442 g, 7.89 mmol) was added and the reaction mixture was heated at reflux overnight. After completion of the reaction, MeOH was concentrated under reduced pressure and the crude mass was cooled to 0° C. and acidified to pH 5 by stirring in 1.5N HCl solution for 15 min. An off white colored solid separated out which was filtered and dried under vacuum to give the title compound (0.16 g, 83.3% yield). 1H NMR (400 MHz, DMSO-d6): δ 1.22-1.23 (d, J=7.2 Hz, 6H), 1.31-1.32 (d, J=6.4 Hz), 4.70-4.75 (m, 1H), 7.26-7.29 (t, J=6.8 Hz, J=7.2 Hz, 2H), 7.40-7.44 (t, J=7.6, J=7.6 Hz, 2H), 7.78-7.80 (d, J=7.6 Hz, 2H), 8.20-8.23 (d, J=13.2 Hz, 2H), 10.95-10.98 (d, J=9.6 Hz, 1H), 12.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[F:15].[C:22]([C:24]1[CH:25]=[C:26]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=1F)#[N:23].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:29]2[CH:28]=[CH:27][C:26]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:25][C:24]=2[C:22]#[N:23])=[CH:10][C:9]=1[F:15])=[O:16]
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3Cl)c(F)c2)c(C#N)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
To a stirred solution of N-(2,4-dichlorophenethyl)-2-fluoro-4-hydroxybenzamide (420 mg, 1.28 mmol) and tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (361 mg, 1.54 mmol) in DMSO (6 ml) was added K2CO3 (265 mg, 1.92 mmol). The reaction was heated stirred at 70° C. for one hour. The reaction was then stirred at 90° C. overnight. The reaction was diluted with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with 10% Na2CO3 and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3-fluorophenoxy)-3-cyanophenyl)acetate (0.0157 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2>>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1C
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Product: Cc1ccccc1[C@@H](C)O

Procedure:
2′-methylacetophenone and (S)-(−)-2-methyl-CBS-oxazaborolidine were reacted as described in Example 35, Step 1 to provide (R)-1-o-Tolyl-ethanol.