Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1>C1COCC1.O>[NH2:25][C:24]([C:21]1[CH:20]=[N:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)=[CH:2][C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C#N)cn1
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(N)=CC#N)cn1
Temperature: 25 °C

Procedure:
A solution of 0.258 ml (1.844 mmol) diisopropylamine in dry THF (1.5 ml) was cooled to −70° C. under inert gas atmosphere, and 1.152 ml (1.844 mmol) n-butyllithium (1.6 M solution in hexanes) were added dropwise. Then, a solution of 85.6 μl (1.627 mmol) acetonitrile in dry THF (1.5 ml) was slowly added over 10 min. The resulting solution was stirred for further 30 min at −70° C. before a solution of 150 mg (1.085 mmol) 2-methoxypyridine-5-carbonitrile in dry THF (1.5 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 h before water (2 ml) was added slowly. The mixture was extracted several times with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 188 mg (99% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].[C:43]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][CH:56]=1)(=[O:46])[CH:44]=[CH2:45]>ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][C:59](=[O:60])[C:58]3[CH:57]=[CH:56][C:55]([O:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:43](=[O:46])[CH:44]=[CH2:45])=[CH:63][CH:62]=3)=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(CCc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)cc2)cc1
Yield: 82.4 %

Procedure:
1.01 g of N,N′-dicyclohexyl carbodiimide was added to a mixture of 1.6 g of 4-{2-[4-(6-acryloyloxy-hexyloxy)-phenyl]-ethyl}-phenol (G), 1.43 g of 4-(6-acryloyloxyhexyloxy)benzoic acid, 0.06 g of 4-N,N-dimethylaminopyridine and 10 ml of dichloromethane stirred in an icebath. After stirring for 2 hours, the ice-bath was removed and the mixture was stirred one night at room temperature. 2.3 g of 4-(6-Acryloyloxy-hexyloxy)-benzoic acid 4-{2-[4-(6-acryloyloxy-hexyloxy)-phenyl]-ethyl}-phenyl ester (10, 78%) was obtained after filtration through silica, evaporation and recrystallizing from methanol.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[CH:26][C:27]=1[F:28].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-chloro-4-fluorophenyl isocyanate (0.17 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a light orange solid (0.16 g, 47% yield), mp=87–89° C.; MS (−) ESI m/z=352 (M−H)−; [α]D25=−23.1° (c=1, EtOH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26])#[N:19]>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([CH:21]=3)[C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-cyano-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.40 (s, 1H), 7.38 (t, J=8.9 Hz, 1H), 7.27 (m, 2H), 7.14 (dd, J=8.6, 2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 3.27 (s, 3H), 1.98 (m, 4H), 0.81 (t, J=7.4 Hz, 6H); MS (ESI) m/z 354 ([M+H]+); MS (ESI) m/z 352 ([M−H]−); Anal. calcd for C20H20FN3O2: C, 67.97H, 5.70; N, 11.89. Found: C, 65.58; H, 5.65; N, 11.36.
Reaction SMILES: CC(OC)(C)C.[CH3:7][OH:8].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[C:22](C#N)=[C:21]([CH3:25])[N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)C(=O)[N:18]2S(C2CC2)(=O)=O)=[C:13]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:12]=1)#[N:10].[CH3:47][OH:48].[C:49](#[N:51])C.CC(OC)(C)C>>[CH3:49][N:51]1[C:7](=[O:8])[C:22]2[C@@H:17]([C:14]3[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=3[S:43]([CH3:46])(=[O:45])=[O:44])[NH:18][C:47](=[O:48])[N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:21]=2[CH2:25]1
Reactant: CC#N
Reactant: CO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)C2CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: COC(C)(C)C
Product: CN1CC2=C(C1=O)[C@@H](c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
(rac)-4-{6-Methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile (Example 34, 190 mg) was separated into the enantiomers by preparative HPLC chromatography on a chiral phase [column: Daicel Chiralpak IC, 5 μm, 250 mm×20 mm; sample preparation: the sample was dissolved in 70 ml of methanol/acetonitrile/MTBE 25:10:35; injection volume: 1 ml; mobile phase: MTBE/methanol 75:25 (0-7 min); flow rate: 15 ml/min; temperature: 30° C.; detection: 220 nm]. This gave 97 mg (100% of theory, >99.0% ee) of the 4S enantiomer. The enantiomeric excess (ee value) was determined chromatographically [column: Daicel Chiralpak IC, 5 μm, 250 mm×4.6 mm; mobile phase: MTBE/methanol 75:25; flow rate: 1 ml/min; temperature: 25° C.; detection: 220 nm; Rt=6.62 min].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 64.5 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70 mmol, prepared according to Example 1, step A), 1,4-dioxane (20 mL), 3-(3-aminophenyl)propan-1-ol (0.16 g, 1.0 mmol, prepared according to Example 12, step A & B), and p-toluenesulfonic acid monohydrate (0.049 g, 0.26 mmol). The mixture was heated at 105° C. for 2 days and NaHCO3 (saturated aqueous solution) was added. The organic solvent was removed under vacuum followed by an addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product (0.18 g, 64%) as a white solid. LCMS for C21H24lN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([NH2:12])=[O:11])=[N:4][C:5](SC)=[N:6][CH:7]=1.[S:13]([O-:18])(O[O-])(=O)=[O:14].[K+].[K+].[C:21](O)(=O)C.CO>O>[Cl:1][C:2]1[C:3]([C:10]([NH2:12])=[O:11])=[N:4][C:5]([S:13]([CH3:21])(=[O:18])=[O:14])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(N)=O)n1
Reactant: CC(=O)O
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ncc(Cl)c(C(N)=O)n1
Reaction time: 3 h
Yield: 17 %

Procedure:
7.7 g (37.8 mmo) of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxamide and 37.2 g (60.4 mmol) of potassium peroxomonosulfate are suspended in a mixture of 30 ml of water, 30 ml of acetic acid and 30 ml of methanol, and the mixture is stirred for about 3 hours. The mixture is then taken up in about 100 ml of water and extracted with ethyl acetate. Drying and concentrating of the ethyl acetate extract gave 1.5 g of 5-chloro-2-(methylsulfonyl)pyrimidine-4-carboxamide (melting point 205° C., 17% yield at a purity of 95%). More 5-chloro-2-(methylsulfonyl)pyrimidine-4-carboxamide was able to be isolated from the mother liquor.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)[CH:8]=2)[N:3]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>C1COCC1>[CH:16]1([CH2:15][O:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:11]([CH:12]=[O:13])=[CH:10]3)[CH2:18][CH2:17]1
Reactant: O=Cc1cc2cc(OCC3CC3)ccc2nc1Cl
Reactant: CC(=O)NCCN
Solvent: C1CCOC1
Product: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1C=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
To a stirred solution of 2-chloro-6-(cyclopropylmethoxy)quinoline-3-carbaldehyde SLA 47086 (770 mg, 2.94 mmol) in THF (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-aminoethyl)acetamide (1.202 g, 11.8 mmol) and the reaction mixture was stirred for 6 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 20 min at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a 10 N aqueous NaOH solution. THF was then evaporated before extraction with CH2Cl2 (100 mL). The separated organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give N-(2-(6-(cyclopropylmethoxy)-3-formylquinolin-2-ylamino)ethyl)acetamide SLA 47092 as a yellow solid (365 mg, 38% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:5]=1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])([O-])=O.CO>C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:4]1[CH:17]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:5]=1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccs2)cc1N
Yield: 41 %

Procedure:
Following the same procedure described for Example 48, step 3 (scheme 36) but substituting compound 171 for compound 299 and using ethyl acetate and triethylamine as a solvent instead methanol, the title compound 300 was obtained in 41% yield over two steps. MS: calc: 305.5; found: 306.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:28][C:29]#[N:30].[NH:31]1C=N[N:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH2:28][C:29]2[NH:30][N:33]=[N:32][N:31]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: c1nnn[nH]1
Reactant: CC(C)c1ccc(-c2ccnc(NS(=O)(=O)c3ccc(Cl)cc3)n2)cc1
Product: CC(C)c1ccc(-c2ccnc(N(Cc3nnn[nH]3)S(=O)(=O)c3ccc(Cl)cc3)n2)cc1

Procedure:
4-Chloro-N-[4-(4-isopropyl-phenyl)-pyrimidin-2-yl]-N-(1H-tetrazol-5-yl methyl)-benzenesulfonamide was prepared from 4-chloro-N-[4-(4-isopropyl-phenyl)-pyrimidin-2yl]-benzenesulfonamide via N-alkylation with bromoacetonitrile using general procedure S (method 1) followed by tetrazole formation using general procedure H. LCMS m/z: 471 (M+1)+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:28][CH2:27][C:13]2[N:14]([C:22]([CH3:26])([CH3:25])[CH:23]=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1>C1COCC1.CCOC(C)=O.O>[CH3:9][N:10]1[CH2:28][CH2:27][C:13]2[N:14]([C:22]([CH3:25])([CH3:26])[CH:23]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1
Reactant: Cc1ccc2c(c1)c1c(n2C(C)(C)C=O)CCN(C)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C(C)(C)C(O)c2ccccc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
Phenyl magnesium bromide (1M solution in THF) (3.7 mL, 3.69 mmol) was added dropwise at −70° C. to a stirred solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-methyl-propionaldehyde (200 mg, 0.73 mmol) in THF (30 mL). The contents were stirred at RT for 16 h, diluted with EtOAc (50 mL) and water (40 mL). The layers were separated and the aqueous layer was again extracted with EtOAc (2×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum to obtain crude compound (300 mg), which was purified by column chromatography on silica gel (100-200 mesh) [Eluent: 0-5% MeOH in DCM] to afford 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-methyl-1-phenyl-propan-1-ol (120 mg) which was repurified by prep. TLC to yield free base (25 mg) compound. The free base was converted into the HCl salt. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.80 (m, 1H), 7.25-7.0 (m, 6H), 6.80 (d, 1H), 5.58 (s, 1H), 4.40 (m, 2H), 4.25 (m, 2H), 3.50 (m, 2H), 2.95 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H), 1.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[NH:5][CH3:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(#N)C>[CH2:11]([N:5]([CH3:6])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CNc1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)c1cc(Cl)cc(Cl)c1

Procedure:
The mixture of 3,5-dichloro-N-methylaniline (345 mg) and excess amount of benzyl bromide and triethylamine in acetonitrile (7 ml) was refluxed for 4 hours. The reaction mixture was separated with ethyl acetate and water, and the organic layer was washed with water, dried and concentrated in vacuo to give N-benzyl-3,5-dichloro-N-methylaniline (532 mg).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH3:12])[N:3]=1.CCO.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C(Cl)Cl.O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:16][CH2:17][CH:18]([OH:20])[CH3:19])[N:4]([CH2:11][CH3:12])[N:3]=1
Reactant: CCn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: CC(O)CN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCn1nc(Br)c([N+](=O)[O-])c1NCC(C)O

Procedure:
A mixture of 3,5-dibromo-1-ethyl-4-nitro-1H-pyrazole (3) (20.0 g; 66.9 mmol), EtOH (100 ml) and 1-amino-2-propanol (25.1 g, 334.2 mmol) was refluxed for 15 hours. The reaction medium was concentrated to the maximum under reduced pressure and the excess 1-amino-2-propanol was then distilled off under vacuum. The oil obtained was suspended in DCM (100 ml) and water (100 ml). The aqueous phase was washed with DCM (100 ml). The combined organic phases were washed with water (50 ml) and were then dried over NaSO4. After evaporating off the solvent under reduced pressure, a brown solid was obtained (19.1 g), which was purified by chromatography on silica gel (eluent: EtOAc/hexane). After recrystallization of the solid from an EtOAc/hexane mixture (13 ml/20 ml), the 1-(5-bromo-2-ethyl-4-nitro-2H-pyrazol-3-ylamino)propan-2-ol was obtained in the form of a yellow solid (7.1 g, 36%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=O.[ClH:13].NO.C[N:17]([CH:19]=O)C>O>[Cl:13][C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:19]#[N:17]
Reactant: CN(C)C=O
Reactant: CC(=O)C(C)(C)C
Reactant: Cl
Agent: NO
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(Cl)=CC#N
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To an ice cold (0-5° C.) dimethylformamide (6.2 mL, 80 mmol) was added phosphorous oxychloride (3.75 mL, 40 mmol) dropwise with stirring for 15 min. To this cold mixture, tert-butyl methyl ketone (2.0 g, 20 mmol) was added dropwise maintaining the temperature of the reaction mixture between 45-55° C. for 10 min. The reaction mixture was slowly allowed to room temperature (rt) and stand for 30 min. To the reaction mixture, 1 mL of a total solution of hydroxylamine hydrochloride (5.56 g, 80 mmol) in dry DMF (8 mL) was added and the mixture was stirred at 70-80° C. for 5 min. Then the remaining solution of hydroxylamine hydrochloride in DMF was added thereafter at such a rate that the temperature of the reaction mixture rise above 145-155° C. After completion of the addition, the reaction mixture was allowed to rt for 30 min and diluted with cold water (200 mL). The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel using hexane-ethyl acetate (98:2) as eluent to give the product as a light green color oil (1.0 g, 35%). 1H NMR (400 MHz, CDCl3): δ 5.56 (1H, s, ═CH), 1.24 (9H, s, tert-butyl).
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C:7](=[CH:8][CH:9]=[C:10]3[C:19]=2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[CH:14]2)[CH:6]=1)(=O)C.[C:23]([O-])(=O)C>>[CH2:23]=[C:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@@H:20]1[C:7](=[CH:6][C:5](=[O:4])[CH2:22][CH2:21]1)[CH2:8][CH2:9]3
Reactant: CC(=O)[O-]
Reactant: CC(=O)Oc1ccc2c3c(ccc2c1)[C@@H]1CC=C[C@@]1(C)CC3
Product: C=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
ESTRA-1,3,5,7,9,16-HEXAEN-3-YL ACETATE (Acetate of E10/N1)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]2[N:18]=[C:17]([NH:19][C:20]([N:22]3CC[CH:24]([NH2:27])[CH2:23]3)=[O:21])[S:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[C:37]([F:40])([F:39])[F:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>CO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:27][CH2:24][CH2:23][NH:22][C:20]([NH:19][C:17]2[S:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([O:9][CH3:8])[C:11]=3[N:18]=2)=[O:21])=[CH:31][C:30]=1[C:37]([F:38])([F:39])[F:40]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(N)C3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ncnc2sc(NC(=O)NCCNCc3ccc(F)c(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A solution of the trifluoroacetic acid salt of 3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (176 mg, 0.46 mmol) in methanol (6 ml), 4-fluoro-3-(trifluoromethyl) benzaldehyde (90 mg, 0.46 mmol) and sodium triacetoxyborohydride (293 mg, 1.38 mmol) at 25° C. The resulting solution was stirred at 25° C. overnight. At this time, the reaction mixture was treated with triethylamine (200 mL, 1.44 mmol) and then was stirred for an additional 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 95/5 methylene chloride/methanol) afforded 1-[2-(4-fluoro-3-trifluoromethyl-benzylamino)-ethyl]-3-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-urea (37 mg, 18%); ES-HRMS m/e calcd for C17H16F4N6O2S (M+H)+ 445.1065, found 445.1065.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH:35]([F:37])[F:36])[CH:32]=4)[N:27]([CH2:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][CH:35]([F:36])[O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH2:38][CH2:39][CH2:40][N:41]([CH3:42])[CH3:43])[N:26]=[C:25]2[C:22]1[N:21]=[C:20]2[C:16]([C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]2=[N:24][CH:23]=1
Reactant: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To the solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (88 mg, 0.12 mmol) in 3 mL of dichloromethane was added 3 mL of trifluoroacetic acid. The reaction mixture was stirred overnight at room temperature. After solvent evaporation, the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (22 mg, 34.5%). LCMS: (M+H)+=502; 1H NMR (300 MHz, CD3OD): δ 9.04 (s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.66 (d, 1H, J=8.7 Hz), 7.35 (d, 1H, J=8.1 Hz), 6.85 (t, 1H, J=74.1 Hz), 4.59 (s, 2H), 3.84 (s, 2H), 3.34-3.32 (m, 2H), 2.89 (s, 6H), 2.44 (s, 2H), 1.64 (s, 6H).
Reaction SMILES: C([Cl:3])=C.[Cl:4]Cl.[Cl-:6].[Cl-:7].[CH2:8]([O:11][P:12](=[O:15])(O)[OH:13])[CH2:9]C>>[Cl-:3].[Cl-:4].[Cl:6][CH:8]([O:11][PH:12](=[O:15])[OH:13])[CH2:9][Cl:7]
Reactant: CCCOP(=O)(O)O
Reactant: C=CCl
Reactant: ClCl
Agent: [Cl-]
Product: O=[PH](O)OC(Cl)CCl

Procedure:
20 g of vinyl chloride and 20 g of chlorine are passed into 20 g of phosphoric acid monopropyl ester-dichloride, the reaction temperature being kept between 0° C. and +10° C. by cooling. Working up by the distillation gives 16g (=62.5% of theory) of phosphonic acid (1,2-dichloroethyl) ester-dichloride, which has a boiling range of 56° - 60° C./0.1 mm Hg.