Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)[C:5]([F:22])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[NH2:28].O.[OH-].[Na+]>CN1CCCC1=O>[F:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)=[N:7][C:2]([NH:28][C:27]2[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:25]([O:24][CH3:23])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CC1(C)Oc2ccc(Nc3nc(Cl)ncc3F)nc2NC1=O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)NC(=O)C(C)(C)O4)n2)cc(OC)c1OC
Temperature: 120 °C
Yield: 160270.8 %

Procedure:
6-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step A) (568 kg, 1.00 mol eq) is mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq) in N-methylpyrrolidin-2-one (2835 kg) with stirring under a nitrogen atmosphere. To this is added water (11 kg) and the mixture heated to about 120° C. and stirred for about 10 hours. This is then cooled to about 65° C. and the pH adjusted to pH 8.5 with 4% w/w aqueous sodium hydroxide solution. The resulting slurry is further cooled to about 20° C., stirred for at least 6 hours and then filtered. The filtered solid is washed twice with water (2×1440 kg) then twice with acetone (2×1140 kg) and finally dried under vacuum at about 40° C. to give the title compound (754 kg, 91%) as a colored solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15]O)([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCOCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][S:25]([CH3:24])(=[O:27])=[O:26])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(CS(C)(=O)=O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
To a 0° C. stirred solution of Intermediate 55 (0.844 g, 3.68 mmol) in dry CH2Cl2 (25 ml) was added Et3N (0.513 ml, 3.682 mmol) and the reaction was stirred for 15 minutes. Methansulfonyl chloride (0.285 ml, 3.682 mmol) was added dropwise and the reaction was allowed to warm to room temperature overnight with good stirring. The reaction was complete by TLC, and Et2O (100 ml) was added. The mixture was filtered and the filter caked was washed with additional Et2O. The filtrate was then concentrated under reduced pressure. The residue was chromatographed with hexanes/EtOAc (0→25%) to yield 1.05 g (93.1%) of 3-methanesulfonylmethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 56). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (s, 3H), 1.4 (m, 1H), 1.4 (s, 9H), 1.6 (m, 3H), 3.0 (s, 3H), 3.2 (s, 1H), 3.5 (s, 2H), 4.0 (d, J=2.4 Hz, 2H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:51][OH:52])[CH:11]([CH3:50])[O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:51][OH:52])([CH:11]([CH3:50])[O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC(C)[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC(C)[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.7 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-7-methyl-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 8c (258 mg, 0.37 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 15 mL) were added o-dichlorobenzene (0.21 mL, 1.82 mmol) and 10% Pd/C (19.3 mg, 0.18 mmol) in turn. The mixture was stirred at room temperature under H2 for 4.5 hours and filtered. The filter cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The combined filtrates were concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound 8 as white powder (98 mg, 59%, HPLC: 97.2%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 451.1[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.43-7.36 (m, 2H), 7.30 (d, 1H), 7.09 (d, 2H), 6.82 (d, 2H), 5.15 (d, 1H), 4.99 (d, 1H), 4.92 (d, 1H), 4.74 (t, 1H), 3.96 (m, 5H), 3.76 (dd, 1H), 3.62 (m, 2H), 3.51 (dd, 1H), 3.40 (d, 1H), 1.36 (d, 3H), 1.29 (t, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:33][CH:34]([CH3:43])[C:35](N1CCNCC1)=[O:36]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:35](=[O:36])[CH:34]([CH3:43])[CH3:33])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Yield: 91 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and 1-(2-methylpropanoyl)-piperazine to afford the desired product as light-brown foam (91%). MS (ISP): 454.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([NH:9][CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([OH:28])[CH2:26]Br>O>[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([N:9]([CH2:26][CH2:25][OH:28])[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NCCNS(C)(=O)=O)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(N(CCO)CCNS(C)(=O)=O)cc1
Reaction time: 48 h

Procedure:
0.037 mol (10 g) of 4-acetylamino-N-(β-mesylaminoethyl)-aniline is dissolved in 31 ml of boiling water. 7.4 g of sodium carbonate and 0.148 mol (18.5 g) of glycol bromohydrin are added, whilst stirring. After stirring for 4 hours in a boiling water bath, the reaction medium is filtered and the filtrate is then left to stand for 48 hours at 0° C. The 4-acetylamino-N-(β-hydroxyethyl)-N-mesylaminoethylaniline which has precipitated in crystalline form is filtered off. After recrystallisation from boiling water and drying in vacuo, the product melts at 118° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[N:11]OS(C)(=O)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[S-:24][C:25]#[N:26].[Na+].[Br:28][C:29]1[CH:30]=[C:31]([O:36]C2C=CN=NC=2C)[C:32]([NH2:35])=[N:33][CH:34]=1>C(#N)C.O>[Br:28][C:29]1[CH:30]=[C:31]([OH:36])[C:32]([NH:35][C:25]2[S:24][N:11]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[N:26]=2)=[N:33][CH:34]=1
Reactant: Cc1nnccc1Oc1cc(Br)cnc1N
Reactant: N#C[S-]
Reactant: CC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3O)n2)CC1
Temperature: 40 °C
Yield: 51.7 %

Procedure:
1-Acetyl-N-(methylsulfonyloxy)piperidine-4-carbimidoyl chloride (0.15 g, 0.53 mmol), pyridine (0.13 ml, 1.6 mmol), and sodium thiocyanate (0.043 g, 0.53 mmol) were dissolved in acetonitrile (5 mL). The solution was heated to 40° C. for 40 minutes. 5-Bromo-3-(3-methylpyridazin-4-yloxy)pyridin-2-amine (0.10 g, 0.35 mmol) was added and the reaction was heated at 60° C. overnight. The solution was cooled and charged with water. The solid was filtered and dried to give 1-(4-(5-(5-bromo-3-hydroxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.072 g, 51%).
Reaction SMILES: [NH2:1][OH:2].Cl.C([O-])([O-])=O.[K+].[K+].[O:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[C:11]1[C:19]#[N:20]>O.CCO>[OH:2][NH:1][C:19]([C:11]1[O:10][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=1)=[NH:20]
Reactant: N#Cc1cc2cnccc2o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cc2cnccc2o1
Temperature: 70 °C

Procedure:
A solution of NH2OH.HCl (1.22 g, 17.5 mmol) and K2CO3 (1.21 g, 8.75 mmol) in H2O (3 mL) was added to a stirred solution of furo[3,2-c]pyridine-2-carbonitrile (1.26 g, 8.75 mmol) in EtOH (6 mL). The reaction was heated to 70° C. for 2 h, before being concentrated in vacuo. The remainder was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc (8×), then the combined organic extracts were washed with brine, back-extracting with EtOAc (4×). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES+)=178.0 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH:26]([O:29][CH2:30]Cl)([CH3:28])[CH3:27]>C1COCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:30][O:29][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:24][CH3:25]
Reactant: CC(C)OCCl
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)COC(C)C
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.6 mL diisopropylamine in 40 mL of dry THF at −20° C. was added dropwise first 12.0 ml of 2.5 M butyllithium and then 8.1 ml of tributyltinhydride. After 10 min this solution was cooled to −78° C., and 3.25 g of chloromethyl isopropyl ether (Molina et al, 1982 Synthesis, 944) was added dropwise. After 10 min the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 1.5 h. The mixture was poured onto water and extracted with hexanes and the extracts were dried over sodium sulfate and evaporated. The crude product was distilled (0.2 mm, 110-130° C.) to afford 7.8 g of tributyl (isopropoxymethyl)tin as a colorless liquid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[OH:4][C@@:5]1([CH3:26])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[C:13](=[CH2:25])[CH2:12]3.Cl>N1C=CC=CC=1.COC=O.C(OCC)(=O)C>[OH:4][C@@:5]1([CH3:26])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])/[C:17](=[CH:1]\[OH:2])/[CH2:18]1)[C:13](=[CH2:25])[CH2:12]3
Reactant: C[O-]
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(C)O)[C@@]2(C)CCC(=O)C=C12
Agent: Cl
Agent: [Na+]
Solvent: COC=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(C)O)[C@@]2(C)C/C(=C/O)C(=O)C=C12
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
At room temperature, 2.2 g of sodium methylate is added to 3.0 g of 17β-hydroxy-17α-methyl-6-methyleneandrost-4-en-3-one (Tetrahedron 20: 597, 1964) in 70 ml of pyridine and 10.2 ml of formic acid methyl ester. After 18 hours, the reaction mixture is stirred into ice/water which contains hydrochloric acid. The precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate. Chromatography of the crude product on silica gel with a methylene chloride-(tert-butyl methyl ether) gradient yields 2.1 g of (Z)-17β-hydroxy-2-hydroxymethylene-17α-methyl-6-methyleneandrost-4-en-3-one as a foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[N:26]=[CH:25][C:24]([C@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:29][C@@H:27]([C:24]3[CH:25]=[N:26][C:21]([C:20]([F:31])([F:19])[F:30])=[CH:22][CH:23]=3)[CH3:28])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2c1CN(Cc1ccccc1)CC2)c1ccc(C(F)(F)F)nc1
Yield: 90.8 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.00 g, 19.2 mmol), (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (4.76 g, 25.0 mmol), N,N-diisopropylethylamine (6.71 mL, 38.5 mmol), and acetonitrile (15 mL) were divided evenly between two 20 mL microwave vials. The reactions were subjected to microwave irradiation at 200° C. for 3.5 h. The two reactions were mixed together and evaporated the acetonitrile off. The residue was redissolved in CH2Cl2 (150 mL) and washed with 1M NaH2PO4 (2×50 mL). The product was extracted with 1M HCl (2×50 mL). The aqueous extracts were basified to pH 14 and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried with Na2SO4, filtered and evaporated to produce a yellow to orange solid (7.21 g). The crude product was washed with ether (25 mL) by stirring the solids for about 30 minutes. The solids were filtered from the ether and washed with ether (2×5 mL) to obtain a pale yellow powder (3.55 g, 45% yield). The ether filtrate was absorbed onto silica and purified by column with MeOH/CH2Cl2 (0-10%) to yield more product (2.38 g, 30% yield; 75% combined yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[C:12]12([NH2:17])[CH2:16][CH:14]([CH2:15]1)[CH2:13]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:12]12([NH:17][C:5]3[N:4]=[C:3]([S:9][CH3:10])[C:2]([Br:1])=[CH:7][N:6]=3)[CH2:16][CH:14]([CH2:15]1)[CH2:13]2
Reactant: CSc1nc(Cl)ncc1Br
Reactant: NC12CC(C1)C2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(NC23CC(C2)C3)ncc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 104.5 %

Procedure:
To a stirring solution of 5-bromo-2-chloro-4-(methylthio)pyrimidine (1.0 g, 4.18 mmol) in NMP (10.0 mL) was added bicyclo[1.1.1]pentan-1-amine hydrochloride (749 mg, 6.26 mmol, prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (2.19 mL, 12.53 mmol). The mixture was stirred at 100° C. for 16 h and then the solvent was removed under reduced pressure. The residue was diluted in 100 mL ethyl acetate and 50 mL 1M aqueous solution of sodium hydrogen phosphate. The layers were separated and the aqueous layer was extracted with 50 mL ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford N-(bicyclo[1.1.1]pentan-1-yl)-5-bromo-4-(methylthio)pyrimidin-2-amine (1250 mg, 4.37 mmol, 105% yield) as a solid that was used without further purification. MS (ESI) m/z 286.0 [M+1]+ and 288.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1)=[O:7].O.[OH-].[Li+].C1COCC1.Cl>O>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reaction time: 2 h

Procedure:
To a one liter three neck flask was charged the product of Example 73C (50 g, 0.153 mol), lithium hydroxide monohydrate (13 g, 0.310 mol), 200 ml THF and 190 ml water. This hazy solution was stirred for 2 hours. The reaction was quenched with a solution of conc. HCl (32.4 g, 0.329 mol) in 65 mL water, the THF was removed under vacuum and the product extracted into methylene chloride (3×210 ml). (NOTE: If necessary, the pH of the aqueous layer should be adjusted to maintain pH 1-4 during the extractions.) The combined organics were then dried with 50 g sodium sulfate, filtered with a 150 ml methylene chloride rinse of the sodium sulfate, and the solvent was removed under vacuum. The product was dissolved in 450 ml THF and again the solvent was removed. Next the product was dissolved in 475 ml THF containing 0.12 g butylated hydroxytoluene (BHT) for storage. If desired, the solvent can be removed under vacuum and the residual syrup dried in a vacuum oven at 55° C. to provide a glassy solid.
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16]C)=[O:14])=[C:5](O)[CH:4]=1.[OH-].[K+].Cl.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:34]>C(O)C.O>[Cl:34][C:5]1[CH:4]=[C:3]([C:2]([Cl:1])([F:20])[F:19])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CCO
Product: COC(=O)c1c(Cl)cc(C(F)(F)Cl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
A mixture of 5.0 g (0.016 mol) of product of Example 5, 8.38 g (0.154 mol) of KOH, 45 ml of water in 100 ml of ethanol were refluxed for 16 hours. The reaction mixture was poured into 250 ml of water containing 50 ml of HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 3.35 g of solid. Then 45 ml of SOCl2 was added to the solid and this was refluxed for 2 hours. Reaction mixture was concentrated in vacuo and 45 ml of methanol was added to the residue and refluxed for 16 hours. Reaction mixture was concentrated in vacuo. The residue was dissolved in ether, extracted with 10% K2CO3, and water. The combined aqueous layers were acidified with concentrated HCl, extracted with ether, dried (MgSO4) and concentrated in vacuo to 2.11 g of white solid. To this solid was added 1.21 ml (0.010 mol) of 2,6 -lutidine and 20 ml of POCl3. This was refluxed for 16 hours. The reaction mixture was concentrated in vacuo. The residue was poured into water, extracted with ether, washed with 10% HCl, dried (MgSO4) and concentrated in vacuo to 2.17 g of brown oil. Then 50 ml of MeOH was added and this was refluxed for 31/2 hours and then stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo to 1.88 g of crude produt. Kugelrohr distillaton at 47 Pa, pot temperature 80° C., afforded 1.55 g (68.3%) of product as a clear oil, nD25 1.4493.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([CH:12]3[C:17](=[O:18])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=4)[CH2:15][CH:14]=[C:13]3[CH3:33])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CO.C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:17](=[O:18])[N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=4)[CH:15]=[CH:14][C:13]=3[CH3:33])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC1=CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)C(=O)C1N1CCc2nc(N)ncc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn(-c2ccc(N)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Tert-butyl (4-(5-(2-amino-7,8-dihydropyrido[4,3-d]p yrimidin-6(5H)-yl)-4-methyl-6-oxo-5,6-dihydropyridin-1(2H)-yl)phenyl)carbamate (150 mg, 0.334 mmol) was dissolved into a 1:1 mixture of MeOH/THF (˜10 mL) and treated with CF3COOH drop wise and the reaction was allowed to stir for 4 h. One the reaction was completed, the residual CF3COOH was neutralized with NaHCO3 (aq). The reaction was then extracted with EtOAc (3×10 mL) and brine (˜10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and then concentrated in vacuo. The crude organic oil was then purified via column chromatography (MeOH/CHCl3 gradient). Concentration of the appropriate fractions provided the title compound (102 mg, 88%). 1H NMR (DMSO) δ: 7.92 (s, 1H), 7.45-7.52 (m, 2H), 7.41 (d, J=6.7 Hz, 1H), 7.24-7.31 (m, 2H), 6.28 (s, 2H), 6.17 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 2.66 (t, j=5.3 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:23])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:11][N:10]3[CH2:27][CH2:26][CH2:25][O:23][C:9]=23)=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: CS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Product: CS(=O)(=O)c1ccc(-c2nn3c(c2-c2ccc(F)cc2)OCCC3)cc1

Procedure:
Alternatively, the desired compound was prepared according to the method of Example 5D, starting with 4-(4-fluorophenyl)-3-hydroxy-5-(4-(methylsulphonyl)phenyl)-pyrazole and substituting 1,3-dibromopropane in place of 1,2-dibromo ethane (yield: 150 mg, 81%). MS (APCI+) m/z 373 (M+H)+; (APCI−) m/z 371 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ2.27 (m, 2H), 3.23 (s, 3H), 4.20 (t, J=7 Hz, 2H), 4.38 (d, J=7 Hz, 2H), 7.20 (m, 4H), 7.60 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H); Anal. calc. for C19H17FN2O3S; C, 61.27; H, 4.60; N, 7.52. Found: C, 60.93; H, 4.48; N, 7.34.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](O)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.Cl.[F:34][C:35]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[F:34][C:35]1([F:41])[CH2:40][CH2:39][N:38]([C:16]2[CH:15]=[C:14]([F:20])[C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([C:29]5[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:9][CH:10]=4)[C@@:5]4([CH2:4][S:3][C:2]([NH2:1])=[N:22]4)[C:18]=3[CH:17]=2)[CH2:37][CH2:36]1
Reactant: FC1(F)CCNCC1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cccnc1F
Agent: Cl
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(N3CCC(F)(F)CC3)cc12

Procedure:
The titled compound was synthesized by stpes analogous to those described in method AA20 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), 2-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine hydrochloride. MS m/z=501.0.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:65][CH:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (t, J=6.7 Hz, 3 H) 1.60 (m, 6 H) 1.74 (m, 4 H) 1.95 (m, 4 H) 2.18 (s, 3 H) 2.79 (d, J=10.6 Hz, 2 H) 3.73 (m, 1 H) 4.05 (t, J=13.9 Hz, 2 H) 4.19 (d, J=7.1 Hz, 2 H) 4.74 (m, 1 H) 7.40-7.59 (m, 2 H) 7.91 (s, 1 H) 8.11 (d, J=7.6 Hz, 1 H) 8.26 (m, 2 H). [M+H] calc'd for C28H37F2N7O3, 558; found 558.